{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:01:32Z","timestamp":1790863292331,"version":"4.1.0"},"reference-count":139,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["56\/8\/2019-HAE\/BMS"],"award-info":[{"award-number":["56\/8\/2019-HAE\/BMS"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]},{"award":["56\/8\/2019-HAE\/BMS"],"award-info":[{"award-number":["56\/8\/2019-HAE\/BMS"]}],"id":[{"id":"https:\/\/ror.org\/0492wrx28","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Philadelphia chromosome-positive (Ph+) B-cell acute lymphoblastic leukemia (ALL), driven by the BCR-ABL1 fusion, remains highly aggressive, with poor prognosis despite tyrosine kinase inhibitor (TKI) therapy. Aberrant PI3K\/Akt\/mTOR pathway activation contributes to resistance, warranting identification of predictive kinase biomarkers. To identify and validate critical phospho-kinase markers within the PI3K\/Akt\/mTOR axis as candidate adaptive signaling nodes and exploratory prognostic markers in Ph+ B-ALL. Network pharmacology using STRING and Cytoscape mapped the protein\u2013protein interactions, identifying high-centrality nodes. Functional enrichment analyses (GO\/KEGG) were then performed via ShinyGO. Experimentally, phospho-kinase arrays profiled 39 kinase phosphorylation sites in Ph+ B-ALL cells (SUPB-15) treated with PI3K\/Akt\/mTOR inhibitors (Rapamycin, GDC-0941, GSK690693, Perifosine). Gene expression was validated by RT-qPCR in 100 Ph+ B-ALL patients and protein validation employed Western blot in 50 patient samples with 15 and five healthy controls, respectively. Network analysis identified CREB1 and GSK3 isoforms as central hub regulators. Phospho-kinase profiling revealed p-CREB (Ser133) phosphorylation upregulation following Perifosine, GDC-0941, and Rapamycin treatment, with no statistically significant change after GSK690693. p-GSK3\u03b1\/\u03b2 (Ser21\/9) phosphorylation showed a statistically significant increase after Perifosine, with non-significant trends after GDC-0941, and a significant reduction following Rapamycin. Hierarchical clustering then divided proteins into four distinct clusters positioning CREB1 in cluster 3 and GSK3\u03b1\/\u03b2 in cluster 2 as candidate adaptive response markers based on their phosphorylation profiles. RT-qPCR demonstrated marked downregulation of GSK3\u03b1 (approximately 71%), GSK3\u03b2 (63%), and CREB1 (65%) transcripts in patients versus controls, with even greater suppression seen in cell lines. Conversely, Western blot revealed a significant 2.49 fold elevated p-CREB (Ser133) (\u03b2 = 1.317, p = 0.000347) and a phospho-GSK3\u03b1\/\u03b2 (Ser21\/9) level that did not differ significantly between patients and controls (\u03b2 = 0.467, p = 0.466), revealing mRNA\u2013protein discordance indicative of compensatory post-transcriptional and post-translational regulation. These findings represent treatment-associated and disease-state associations between altered phosphorylation states and the Ph+ B-ALL context; functional validation remains an essential next step. mRNA\u2013protein discordance with transcriptional downregulation (63\u201371%) contrasting with elevated p-CREB levels (2.49-fold, p = 0.000347) suggests post-translational compensatory mechanisms under therapeutic pressure. CREB1 and GSK3 isoforms emerge as central network nodes that might potentially mediate adaptive resistance, although functional validation is required. It should be noted that the evidence presented is associative rather than causal and a direct link between the observed phosphorylation changes and clinical drug resistance has not been established in this study. Sustained CREB phosphorylation despite PI3K\/Akt\/mTOR inhibition implicates alternative kinase pathways (MAPK\/ERK, CaMK), supporting rational combination therapy strategies. These findings position p-CREB and p-GSK-3\u03b1\/\u03b2 as candidate biomarkers, highlighting the value of phospho-proteomics over transcriptomics alone in capturing pathway activation. Multi-omics integration may prove essential for overcoming adaptive resistance in ALL patients.<\/jats:p>","DOI":"10.3390\/ijms27188300","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:18:26Z","timestamp":1790860706000},"page":"8300","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CREB1 and GSK3 Isoforms as Potential Adaptive Signaling Nodes in PI3K\/Akt\/mTOR Inhibitor Treated Philadelphia Chromosome-Positive B-ALL"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6916-014X","authenticated-orcid":false,"given":"Himanshu","family":"Dhanda","sequence":"first","affiliation":[{"name":"ICMR-Centre for Cancer Pathology, New Delhi 110029, India"},{"name":"Manipal Academy of Higher Education, Manipal 576104, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamsuz","family":"Zaman","sequence":"additional","affiliation":[{"name":"ICMR-Centre for Cancer Pathology, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep Kumar","family":"Swain","sequence":"additional","affiliation":[{"name":"ICMR-National Institute of Child Health Research, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neetu","family":"Kushwaha","sequence":"additional","affiliation":[{"name":"ICMR-National Institute of Child Health Research, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raj","family":"Kamal","sequence":"additional","affiliation":[{"name":"ICMR-National Institute of Child Health Research, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manpreet","family":"Kaur","sequence":"additional","affiliation":[{"name":"ICMR-National Institute of Child Health Research, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5367-6050","authenticated-orcid":false,"given":"Bhavika","family":"Rishi","sequence":"additional","affiliation":[{"name":"ICMR-National Institute of Child Health Research, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2357-976X","authenticated-orcid":false,"given":"Pranay","family":"Tanwar","sequence":"additional","affiliation":[{"name":"Dr. B.R.A. Institute of Rotary Cancer Hospital, All India Institute of Medical Science, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8044-4327","authenticated-orcid":false,"given":"Sufian","family":"Zaheer","sequence":"additional","affiliation":[{"name":"Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4440-5339","authenticated-orcid":false,"given":"Amitabh","family":"Singh","sequence":"additional","affiliation":[{"name":"Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1964-2014","authenticated-orcid":false,"given":"Sumita","family":"Chaudhry","sequence":"additional","affiliation":[{"name":"Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7643-7936","authenticated-orcid":false,"given":"Fouzia","family":"Siraj","sequence":"additional","affiliation":[{"name":"ICMR-Centre for Cancer Pathology, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2884-3600","authenticated-orcid":false,"given":"Aroonima","family":"Misra","sequence":"additional","affiliation":[{"name":"ICMR-National Institute of Child Health Research, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1016\/S0140-6736(19)33018-1","article-title":"Acute lymphoblastic leukaemia","volume":"395","author":"Malard","year":"2020","journal-title":"Lancet"},{"key":"ref_2","unstructured":"Howlader, N., Noone, A.M., Krapcho, M., Miller, D., Brest, A., Yu, M., Ruhl, J., Tatalovich, Z., Mariotto, A., and Lewis, D.R. (2017). SEER Cancer Statistics Review, 1975\u20132014, National Cancer Institute."},{"key":"ref_3","first-page":"7","article-title":"Cancer statistics, 2018","volume":"68","author":"Siegel","year":"2018","journal-title":"CA A Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1182\/blood-2008-06-164863","article-title":"Improvement in survival in younger patients with acute lymphoblastic leukemia from the 1980s to the early 21st century","volume":"113","author":"Pulte","year":"2009","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Pulte, D., Pulte, D., Jansen, L., Gondos, A., Katalinic, A., Barnes, B., Ressing, M., Holleczek, B., Eberle, A., and Brenner, H. (2014). The GEKID Cancer Survival Working Group. Survival of adults with acute lymphoblastic leukemia in Germany and the United States. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0085554"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1200\/JCO.2011.37.8018","article-title":"Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: A report from the children\u2019s oncology group","volume":"30","author":"Hunger","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e202","DOI":"10.1016\/S2352-3026(17)30052-2","article-title":"Worldwide comparison of survival from childhood leukaemia for 1995\u20132009, by subtype, age, and sex (CONCORD-2): A population-based study of individual data for 89828 children from 198 registries in 53 countries","volume":"4","author":"Bonaventure","year":"2017","journal-title":"Lancet Haematol."},{"key":"ref_8","first-page":"e62557","article-title":"Leukemia in India: Insights Into Incidence, Prevalence, Mortality, and Disability-Adjusted Life Years","volume":"16","author":"Nalage","year":"2024","journal-title":"Cureus"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e85","DOI":"10.1016\/j.clml.2020.08.023","article-title":"Systematic Review of the Burden and Treatment Patterns of Adult and Adolescent Acute Lymphoblastic Leukemia in India: Comprehending the Challenges in an Emerging Economy","volume":"21","author":"Radhakrishnan","year":"2021","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2620","DOI":"10.1182\/blood.V126.23.2620.2620","article-title":"Prognostic Significance of Immunophenotypic Composition of B Cell Acute Lymphoblastic Leukemia at Diagnosis: A Novel Immunophenotype Based Risk Score","volume":"126","author":"Deshpande","year":"2015","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1200\/JCO.2017.74.0449","article-title":"Genotype-Specific Minimal Residual Disease Interpretation Improves Stratification in Pediatric Acute Lymphoblastic Leukemia","volume":"36","author":"Enshaei","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"100593","DOI":"10.1016\/j.lansea.2025.100593","article-title":"Risk stratified treatment for childhood acute lymphoblastic leukaemia: A multicentre observational study from India","volume":"37","author":"Gogoi","year":"2025","journal-title":"Lancet Reg. Health Southeast Asia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1182\/blood.2023022920","article-title":"Classification and risk stratification in T-lineage acute lymphoblastic leukemia","volume":"145","author":"Mullighan","year":"2025","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1002\/cncr.23666","article-title":"Kinase domain point mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia emerge after therapy with BCR-ABL kinase inhibitors","volume":"113","author":"Jones","year":"2008","journal-title":"Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1182\/blood-2006-03-011908","article-title":"Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: Results of the GRAAPH-2003 study","volume":"109","author":"Rousselot","year":"2007","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1056\/NEJMoa1403088","article-title":"Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia","volume":"371","author":"Roberts","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1056\/NEJMoa1306494","article-title":"A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias","volume":"369","author":"Cortes","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2306","DOI":"10.1200\/JCO.2017.76.7228","article-title":"Dasatinib Plus Intensive Chemotherapy in Children, Adolescents, and Young Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Results of Children\u2019s Oncology Group Trial AALL0622","volume":"36","author":"Slayton","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"653","DOI":"10.3324\/haematol.2014.118588","article-title":"Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia","volume":"100","author":"Daver","year":"2015","journal-title":"Haematologica"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4178","DOI":"10.1182\/blood-2008-06-165027","article-title":"Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia","volume":"112","author":"Yang","year":"2008","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1126\/science.1164266","article-title":"Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia","volume":"322","author":"Mullighan","year":"2008","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Simioni, C., Martelli, A.M., Zauli, G., Melloni, E., and Neri, L.M. (2019). Targeting mTOR in Acute Lymphoblastic Leukemia. Cells, 8.","DOI":"10.3390\/cells8020190"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.cell.2006.01.016","article-title":"TOR signaling in growth and metabolism","volume":"124","author":"Wullschleger","year":"2006","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1517\/14728222.2012.677439","article-title":"An overview of the mTOR pathway as a target in cancer therapy","volume":"16","author":"Gentzler","year":"2012","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"909","DOI":"10.3892\/ijo.2014.2525","article-title":"Therapeutic potential of targeting mTOR in T-cell acute lymphoblastic leukemia (review)","volume":"45","author":"Evangelisti","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/leu.2013.226","article-title":"Targeting the PI3K\/Akt\/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential","volume":"28","author":"Neri","year":"2014","journal-title":"Leukemia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.3324\/haematol.2013.096438","article-title":"Adult B-cell acute lymphoblastic leukemia cells display decreased PTEN activity and constitutive hyperactivation of PI3K\/Akt pathway despite high PTEN protein levels","volume":"99","author":"Gomes","year":"2014","journal-title":"Haematologica"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/pbc.24034","article-title":"Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia","volume":"59","author":"Morishita","year":"2012","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Nemes, K., Sebesty\u00e9n, A., M\u00e1rk, \u00c1., Hajdu, M., Kenessey, I., Sticz, T., Nagy, E., Barna, G., V\u00e1radi, Z., and Kov\u00e1cs, G. (2013). Mammalian target of rapamycin (mTOR) activity dependent phospho-protein expression in childhood acute lymphoblastic leukemia (ALL). PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0059335"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1038\/leu.2011.322","article-title":"Silencing of ETV6\/RUNX1 abrogates PI3K\/AKT\/mTOR signaling and impairs reconstitution of leukemia in xenografts","volume":"26","author":"Fuka","year":"2012","journal-title":"Leukemia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1002\/jcp.26135","article-title":"Phosphatidylinositol 3-kinase inhibition potentiates glucocorticoid response in B-cell acute lymphoblastic leukemia","volume":"233","author":"Evangelisti","year":"2018","journal-title":"J. Cell Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.3324\/haematol.2016.146381","article-title":"The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia","volume":"101","author":"Mendes","year":"2016","journal-title":"Haematologica"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8027","DOI":"10.18632\/oncotarget.24261","article-title":"Inhibition of mTORC1\/C2 signaling improves anti-leukemia efficacy of JAK\/STAT blockade in CRLF2 rearranged and\/or JAK driven Philadelphia chromosome-like acute B-cell lymphoblastic leukemia","volume":"9","author":"Zhang","year":"2018","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3510","DOI":"10.1182\/blood-2012-03-415448","article-title":"Targeting JAK1\/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia","volume":"120","author":"Maude","year":"2012","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1038\/sj.bjc.6605072","article-title":"Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism","volume":"100","author":"Beesley","year":"2009","journal-title":"Br. J. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e1470","DOI":"10.1038\/cddis.2014.431","article-title":"Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis","volume":"5","author":"Liu","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/nature21076","article-title":"Metabolic gatekeeper function of B-lymphoid transcription factors","volume":"542","author":"Chan","year":"2017","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3349","DOI":"10.1113\/jphysiol.2010.190926","article-title":"Significance of SGK1 in the regulation of neuronal function","volume":"588","author":"Lang","year":"2010","journal-title":"J. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.18632\/oncotarget.2992","article-title":"mTOR kinase inhibitors synergize with histone deacetylase inhibitors to kill B-cell acute lymphoblastic leukemia cells","volume":"6","author":"Beagle","year":"2014","journal-title":"Oncotarget"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1111\/bjh.14569","article-title":"A phase 1 trial of temsirolimus and intensive re-induction chemotherapy for 2nd or greater relapse of acute lymphoblastic leukaemia: A Children\u2019s Oncology Group study (ADVL1114)","volume":"177","author":"Rheingold","year":"2017","journal-title":"Br. J. Haematol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1038\/s41467-022-28682-1","article-title":"Phosphoproteomic profiling of T cell acute lymphoblastic leukemia reveals targetable kinases and combination treatment strategies","volume":"13","author":"Meijer","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"105171","DOI":"10.1016\/j.ebiom.2024.105171","article-title":"An artificial intelligence-assisted clinical framework to facilitate diagnostics and translational discovery in hematologic neoplasia","volume":"104","author":"Tang","year":"2024","journal-title":"eBioMedicine"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4496","DOI":"10.7150\/ijbs.98899","article-title":"Integrative alternative splicing analysis reveals new prognosis signature in B-cell acute lymphoblastic leukemia","volume":"20","author":"Zhuo","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"101511","DOI":"10.1016\/j.beha.2023.101511","article-title":"Cytogenetics and genomics in pediatric acute lymphoblastic leukaemia","volume":"36","author":"Lentes","year":"2023","journal-title":"Best Pract. Res. Clin. Haematol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Lin, C., Xu, J.-Q., Zhong, G.-C., Chen, H., Xue, H.-M., Yang, M., and Chen, C. (2022). Integrating RNA-seq and scRNA-seq to explore the biological significance of NAD + metabolism-related genes in the initial diagnosis and relapse of childhood B-cell acute lymphoblastic leukemia. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1043111"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1038\/s41467-021-22787-9","article-title":"Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures","volume":"12","author":"Franciosa","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/s41568-022-00454-5","article-title":"Therapy resistance: Opportunities created by adaptive responses to targeted therapies in cancer","volume":"22","author":"Labrie","year":"2022","journal-title":"Nat. Rev. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1038\/s41556-019-0328-z","article-title":"Mapping phospho-catalytic dependencies of therapy-resistant tumours reveals actionable vulnerabilities","volume":"21","author":"Mori","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Carels, N., Sgariglia, D., Junior, M.G.V., Lima, C.R., Carneiro, F.R.G., da Silva, G.F., da Silva, F.A.B., Scardini, R., Tuszynski, J.A., and de Andrade, C.V. (2023). A Strategy Utilizing Protein-Protein Interaction Hubs for the Treatment of Cancer Diseases. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242216098"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4121","DOI":"10.1007\/s00277-024-05821-w","article-title":"Integrated systems biology analysis of acute lymphoblastic leukemia: Unveiling molecular signatures and drug repurposing opportunities","volume":"103","author":"Budak","year":"2024","journal-title":"Ann. Hematol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"eaau2875","DOI":"10.1126\/scisignal.aau2875","article-title":"Systemic analysis of tyrosine kinase signaling reveals a common adaptive response program in a HER2-positive breast cancer","volume":"12","author":"Schwill","year":"2019","journal-title":"Sci. Signal."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Bica, V., Venafra, V., Massacci, G., Graziosi, S., Gualdi, S., Minnella, G., Sor\u00e0, F., Chiusolo, P., Brunetti, M.E., and Napolitano, G. (2025). Phosphoproteomics reveals novel BCR::ABL1-independent mechanisms of resistance in chronic myeloid leukemia. bioRxiv.","DOI":"10.1101\/2025.01.08.631869"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e749","DOI":"10.1002\/ctm2.749","article-title":"Phosphoproteomics profiling reveals a kinase network conferring acute myeloid leukaemia intrinsic chemoresistance and indicates HMGA1 phosphorylation as a potential influencer","volume":"12","author":"Zhu","year":"2022","journal-title":"Clin. Transl. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"981","DOI":"10.3324\/haematol.2022.281177","article-title":"Hyperactive CREB subpopulations increase during therapy in pediatric B-lineage acute lymphoblastic leukemia","volume":"108","author":"Masic","year":"2023","journal-title":"Haematologica"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"12549","DOI":"10.2147\/OTT.S281802","article-title":"Inhibition of CSRP2 Promotes Leukemia Cell Proliferation and Correlates with Relapse in Adults with Acute Myeloid Leukemia","volume":"13","author":"Wang","year":"2020","journal-title":"OncoTargets Ther."},{"key":"ref_56","first-page":"1","article-title":"Inhibiting H3K27 Demethylases Downregulates CREB-CREBBP, Overcoming Resistance in Relapsed Acute Lymphoblastic Leukemia","volume":"14","author":"Alcon","year":"2025","journal-title":"Cancer Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.bbrc.2014.04.125","article-title":"Increased expression of sorcin is associated with multidrug resistance in leukemia cells via up-regulation of MDR1 expression through cAMP response element-binding protein","volume":"448","author":"Yamagishi","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/leu.2010.272","article-title":"PDGFRA rearrangement leading to hyper-eosinophilia, T-lymphoblastic lymphoma, myeloproliferative neoplasm and precursor B-cell acute lymphoblastic leukemia","volume":"25","author":"Huang","year":"2011","journal-title":"Leukemia"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"192","DOI":"10.18632\/aging.100296","article-title":"Roles of the Raf\/MEK\/ERK and PI3K\/PTEN\/Akt\/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging","volume":"3","author":"Steelman","year":"2011","journal-title":"Aging"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/s41392-023-01705-z","article-title":"Targeting the RAS\/RAF\/MAPK pathway for cancer therapy: From mechanism to clinical studies","volume":"8","author":"Bahar","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"8349","DOI":"10.1038\/s41598-020-65061-6","article-title":"ERK Activity in Immature Leukemic Cells Drives Clonal Selection during Induction Therapy for Acute Myeloid Leukemia","volume":"10","author":"Hayun","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1002\/JLB.2A0421-221R","article-title":"Gab2 promotes acute myeloid leukemia growth and migration through the SHP2-Erk-CREB signaling pathway","volume":"112","author":"Gong","year":"2022","journal-title":"J. Leukoc. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Ma, Q., Liu, W., Su, Y., Guo, J., Zhang, M., Guo, J., Liu, M., Dong, W., Li, M., and Wang, B. (2025). Quercetin inhibits the cAMP\/PKA\/CREB\/glycolysis axis to exert anti-acute lymphoblastic leukemia effects. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1614973"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Nasimian, A., Al Ashiri, L., Ahmed, M., Duan, H., Zhang, X., R\u00f6nnstrand, L., and Kazi, J.U. (2023). A Receptor Tyrosine Kinase Inhibitor Sensitivity Prediction Model Identifies AXL Dependency in Leukemia. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043830"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.toxlet.2019.04.004","article-title":"PKA- and Ca2+-dependent p38 MAPK\/CREB activation protects against manganese-mediated neuronal apoptosis","volume":"309","author":"Zhu","year":"2019","journal-title":"Toxicol. Lett."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1152\/physrev.00041.2005","article-title":"Ca2+-operated transcriptional networks: Molecular mechanisms and in vivo models","volume":"88","author":"Savignac","year":"2008","journal-title":"Physiol. Rev."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/s41419-021-03504-2","article-title":"GLI1 reduces drug sensitivity by regulating cell cycle through PI3K\/AKT\/GSK3\/CDK pathway in acute myeloid leukemia","volume":"12","author":"Zhou","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"15330338231207765","DOI":"10.1177\/15330338231207765","article-title":"DUSP1 Signaling Pathway Regulates Cytarabine Sensitivity in Acute Myeloid Leukemia","volume":"22","author":"Sun","year":"2023","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Huang, W., Yang, S., Cheng, Y.-S., Sima, N., Sun, W., Shen, M., Braisted, J.C., Lu, W., and Zheng, W. (2022). Terfenadine resensitizes doxorubicin activity in drug-resistant ovarian cancer cells via an inhibition of CaMKII\/CREB1 mediated ABCB1 expression. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1068443"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2583","DOI":"10.1158\/1078-0432.CCR-08-1137","article-title":"CREB in the pathophysiology of cancer: Implications for targeting transcription factors for cancer therapy","volume":"15","author":"Sakamoto","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"14970","DOI":"10.18632\/oncotarget.3911","article-title":"Essential role for cyclic-AMP responsive element binding protein 1 (CREB) in the survival of acute lymphoblastic leukemia","volume":"6","author":"Kampen","year":"2015","journal-title":"Oncotarget"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2808","DOI":"10.1073\/pnas.051634198","article-title":"Activity-dependent CREB phosphorylation: Convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway","volume":"98","author":"Wu","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ccr.2011.12.015","article-title":"Polycomb-mediated loss of miR-31 activates NIK-dependent NF-\u03baB pathway in adult T cell leukemia and other cancers","volume":"21","author":"Yamagishi","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"35454","DOI":"10.18632\/oncotarget.7721","article-title":"Control of CREB expression in tumors: From molecular mechanisms and signal transduction pathways to therapeutic target","volume":"7","author":"Steven","year":"2016","journal-title":"Oncotarget"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"eabd6280","DOI":"10.1126\/sciadv.abd6280","article-title":"Oxidative phosphorylation enhances the leukemogenic capacity and resistance to chemotherapy of B cell acute lymphoblastic leukemia","volume":"7","author":"Chen","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"5272","DOI":"10.1038\/ncomms6272","article-title":"Kinetic modulation of a disordered protein domain by phosphorylation","volume":"5","author":"Stanley","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Illiano, M., Conte, M., Salzillo, A., Ragone, A., Spina, A., Nebbioso, A., Altucci, L., Sapio, L., and Naviglio, S. (2020). The KDM Inhibitor GSKJ4 Triggers CREB Downregulation via a Protein Kinase A and Proteasome-Dependent Mechanism in Human Acute Myeloid Leukemia Cells. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.00799"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.pharmthera.2014.11.016","article-title":"Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases","volume":"148","author":"Beurel","year":"2015","journal-title":"Pharmacol. Ther."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jbior.2017.05.001","article-title":"GSK-3 as a novel prognostic indicator in leukemia","volume":"65","author":"Ruvolo","year":"2017","journal-title":"Adv. Biol. Regul."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1038\/s41375-021-01243-z","article-title":"GSK-3: A multifaceted player in acute leukemias","volume":"35","author":"Martelli","year":"2021","journal-title":"Leukemia"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Martelli, A.M., Paganelli, F., Evangelisti, C., Chiarini, F., and McCubrey, J.A. (2022). Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies. Cells, 11.","DOI":"10.3390\/cells11111812"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Sapio, L., Salzillo, A., Ragone, A., Illiano, M., Spina, A., and Naviglio, S. (2020). Targeting CREB in Cancer Therapy: A Key Candidate or One of Many? An Update. Cancers, 12.","DOI":"10.1155\/2020\/7262479"},{"key":"ref_83","first-page":"7717","article-title":"Glycogen Synthase Kinase 3 Promotes Tyrosine Kinase Inhibitor-Induced Apoptosis in Philadelphia Chromosome-Positive Leukemia Cells by Regulating the Wnt\/\u03b2-Catenin Pathway","volume":"37","author":"Liang","year":"2023","journal-title":"J. Biol. Regul. Homeost. Agents."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1158\/2767-9764.CRC-23-0379","article-title":"Pim Kinase Inhibitors Increase Gilteritinib Cytotoxicity in FLT3-ITD Acute Myeloid Leukemia Through GSK-3\u03b2 Activation and c-Myc and Mcl-1 Proteasomal Degradation","volume":"4","author":"Lee","year":"2024","journal-title":"Cancer Res. Commun."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1186\/1756-9966-29-154","article-title":"Glycogen synthase kinase-3\u03b2 inhibition induces nuclear factor-\u03baB-mediated apoptosis in pediatric acute lymphocyte leukemia cells","volume":"29","author":"Hu","year":"2010","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.17219\/acem\/63752","article-title":"Glycogen Synthase Kinase-3\u03b2 (GSK-3\u03b2) and Nuclear Factor Kappa-B (NFKB) in Childhood Acute Lymphoblastic Leukemia","volume":"25","author":"Tovar","year":"2016","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1634\/stemcells.2007-0600","article-title":"Glycogen synthase kinase-3beta inhibition preserves hematopoietic stem cell activity and inhibits leukemic cell growth","volume":"26","author":"Holmes","year":"2008","journal-title":"Stem Cells"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1002\/jcp.21848","article-title":"PKR activity is required for acute leukemic cell maintenance and growth: A role for PKR-mediated phosphatase activity to regulate GSK-3 phosphorylation","volume":"221","author":"Blalock","year":"2009","journal-title":"J. Cell. Physiol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.3892\/or.2020.7817","article-title":"Glycogen synthase kinase 3\u03b2 in tumorigenesis and oncotherapy (Review)","volume":"44","author":"He","year":"2020","journal-title":"Oncol. Rep."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1210\/me.2009-0466","article-title":"Glycogen synthase kinase-3 plays a central role in mediating glucocorticoid-induced apoptosis","volume":"24","author":"Spokoini","year":"2010","journal-title":"Mol. Endocrinol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1124\/mol.108.047639","article-title":"Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor (2S)-1-(1H-Indol-3-yl)-3-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl]oxypropan2-amine (A443654) in T-cell acute lymphoblastic leukemia","volume":"74","author":"Blalock","year":"2008","journal-title":"Mol. Pharmacol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1038\/leu.2012.136","article-title":"Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia","volume":"26","author":"Simioni","year":"2012","journal-title":"Leukemia"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1172\/JCI46465","article-title":"The intersection of genetic and chemical genomic screens identifies GSK-3alpha as a target in human acute myeloid leukemia","volume":"122","author":"Banerji","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"8907","DOI":"10.1021\/acs.jmedchem.5b01200","article-title":"Evaluation of Improved Glycogen Synthase Kinase-3\u03b1 Inhibitors in Models of Acute Myeloid Leukemia","volume":"58","author":"Neumann","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1158\/1535-7163.MCT-20-0663","article-title":"PP2A-activating Drugs Enhance FLT3 Inhibitor Efficacy through AKT Inhibition-Dependent GSK-3\u03b2-Mediated c-Myc and Pim-1 Proteasomal Degradation","volume":"20","author":"Scarpa","year":"2021","journal-title":"Mol. Cancer Ther."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/s41420-023-01317-0","article-title":"The GSK3\u03b2\/Mcl-1 axis is regulated by both FLT3-ITD and Axl and determines the apoptosis induction abilities of FLT3-ITD inhibitors","volume":"9","author":"Qiu","year":"2023","journal-title":"Cell Death Discov."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/s41419-022-05178-w","article-title":"GSK3\u03b2 is a critical, druggable component of the network regulating the active NOTCH1 protein and cell viability in CLL","volume":"13","author":"Rompietti","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Kurosu, T., Nagao, T., Wu, N., Oshikawa, G., and Miura, O. (2013). Inhibition of the PI3K\/Akt\/GSK3 pathway downstream of BCR\/ABL, Jak2-V617F, or FLT3-ITD downregulates DNA damage-induced Chk1 activation as well as G2\/M arrest and prominently enhances induction of apoptosis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079478"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.jbior.2017.06.001","article-title":"Casein Kinase II (CK2), Glycogen Synthase Kinase-3 (GSK-3) and Ikaros mediated regulation of leukemia","volume":"65","author":"Gowda","year":"2017","journal-title":"Adv. Biol. Regul."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.jbior.2017.05.002","article-title":"Targeting the Akt, GSK-3, Bcl-2 axis in acute myeloid leukemia","volume":"65","author":"Ricciardi","year":"2017","journal-title":"Adv. Biol. Regul."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"820","DOI":"10.4161\/cc.27728","article-title":"Inhibition of GSK-3\u03b2 activity can result in drug and hormonal resistance and alter sensitivity to targeted therapy in MCF-7 breast cancer cells","volume":"13","author":"Sokolosky","year":"2014","journal-title":"Cell Cycle"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2344","DOI":"10.1128\/MCB.01525-14","article-title":"mTOR Complex 2 Stabilizes Mcl-1 Protein by Suppressing Its Glycogen Synthase Kinase 3-Dependent and SCF-FBXW7-Mediated Degradation","volume":"35","author":"Koo","year":"2015","journal-title":"Mol. Cell Biol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2555","DOI":"10.1158\/0008-5472.CAN-13-2946","article-title":"Maintaining glycogen synthase kinase-3 activity is critical for mTOR kinase inhibitors to inhibit cancer cell growth","volume":"74","author":"Koo","year":"2014","journal-title":"Cancer Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.bbacli.2015.07.001","article-title":"Phosphorylation of GSK3alpha\/beta correlates with activation of AKT and is prognostic for poor overall survival in acute myeloid leukemia patients","volume":"4","author":"Ruvolo","year":"2015","journal-title":"BBA Clin."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1093\/nar\/gkj519","article-title":"Post-transcriptional regulation of thioredoxin by the stress inducible heterogenous ribonucleoprotein A18","volume":"34","author":"Yang","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1073\/pnas.0611015104","article-title":"Cell stress modulates the function of splicing regulatory protein RBM4 in translation control","volume":"104","author":"Lin","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/cdd.2013.135","article-title":"Remodelling of a polypyrimidine tract-binding protein complex during apoptosis activates cellular IRESs","volume":"21","author":"King","year":"2014","journal-title":"Cell Death Differ."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"21705","DOI":"10.3390\/ijms141121705","article-title":"RNA-binding proteins impacting on internal initiation of translation","volume":"14","author":"Lozano","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1261\/rna.780708","article-title":"Identification of PCBP2, a facilitator of IRES-mediated translation, as a novel constituent of stress granules and processing bodies","volume":"14","author":"Fujimura","year":"2008","journal-title":"RNA"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"3764","DOI":"10.1093\/nar\/gkv205","article-title":"DAP5 associates with eIF2\u03b2 and eIF4AI to promote Internal Ribosome Entry Site driven translation","volume":"43","author":"Liberman","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"113283","DOI":"10.1016\/j.celrep.2023.113283","article-title":"The intrinsically disordered region of eIF5B stimulates IRES usage and nucleates biological granule formation","volume":"42","author":"Harris","year":"2023","journal-title":"Cell Rep."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1186\/s13046-023-02810-1","article-title":"RNA binding protein IGF2BP1 synergizes with ETV6-RUNX1 to drive oncogenic signaling in B-cell Acute Lymphoblastic Leukemia","volume":"42","author":"Sharma","year":"2023","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.semcancer.2022.05.009","article-title":"The IGF2BP family of RNA binding proteins links epitranscriptomics to cancer","volume":"86","author":"Guil","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2935","DOI":"10.1038\/s41467-023-38456-y","article-title":"Dasatinib overcomes glucocorticoid resistance in B-cell acute lymphoblastic leukemia","volume":"14","author":"Sarno","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1158\/1541-7786.MCR-19-0217","article-title":"HSF1-Mediated Control of Cellular Energy Metabolism and mTORC1 Activation Drive Acute T-Cell Lymphoblastic Leukemia Progression","volume":"18","author":"Eroglu","year":"2020","journal-title":"Mol. Cancer Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.3109\/10428194.2010.506570","article-title":"Protein kinase networks regulating glucocorticoid-induced apoptosis of hematopoietic cancer cells: Fundamental aspects and practical considerations","volume":"51","author":"Sionov","year":"2010","journal-title":"Leuk. Lymphoma"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1182\/blood-2007-04-083600","article-title":"CREB is a critical regulator of normal hematopoiesis and leukemogenesis","volume":"111","author":"Cheng","year":"2008","journal-title":"Blood"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.1038\/onc.2009.111","article-title":"Fbw7 promotes ubiquitin-dependent degradation of c-Myb: Involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb","volume":"28","author":"Kitagawa","year":"2009","journal-title":"Oncogene"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"e175","DOI":"10.1038\/bcj.2013.67","article-title":"GSK3-mediated MAF phosphorylation in multiple myeloma as a potential therapeutic target","volume":"4","author":"Herath","year":"2014","journal-title":"Blood Cancer J."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1002\/gcc.22264","article-title":"PI3K\/AKT signaling inhibits NOTCH1 lysosome-mediated degradation","volume":"54","author":"Platonova","year":"2015","journal-title":"Genes Chromosom. Cancer"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"111428","DOI":"10.1016\/j.celrep.2022.111428","article-title":"The molecular network of the proteasome machinery inhibition response is orchestrated by HSP70, revealing vulnerabilities in cancer cells","volume":"40","author":"Grochowski","year":"2022","journal-title":"Cell Rep."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1038\/s41591-018-0105-8","article-title":"Oncogenic hijacking of the stress response machinery in T cell acute lymphoblastic leukemia","volume":"24","author":"Kourtis","year":"2018","journal-title":"Nat. Med."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.1182\/blood-2023-184800","article-title":"PTEN Counter Balances mTORC1 and PI3K Activities to Maintain Metabolic Homeostasis of B-ALL","volume":"142","author":"Liu","year":"2023","journal-title":"Blood"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/j.cell.2006.04.031","article-title":"Relief of microRNA-mediated translational repression in human cells subjected to stress","volume":"125","author":"Bhattacharyya","year":"2006","journal-title":"Cell"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1126\/science.1149460","article-title":"Switching from repression to activation: MicroRNAs can up-regulate translation","volume":"318","author":"Vasudevan","year":"2007","journal-title":"Science"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/978-1-4939-7371-2_18","article-title":"Analysis of MicroRNA-Mediated Translation Activation of In Vitro Transcribed Reporters in Quiescent Cells","volume":"Volume 1686","author":"Bukhari","year":"2018","journal-title":"Cellular Quiescence: Methods and Protocols"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"871","DOI":"10.4161\/rna.20806","article-title":"MicroRNA-mediated posttranscriptional mechanisms of gene expression in proliferating and quiescent cancer cells","volume":"9","author":"Letonqueze","year":"2012","journal-title":"RNA Biol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1158\/0008-5472.CAN-08-3404","article-title":"MiR-34b targets cyclic AMP-responsive element binding protein in acute myeloid leukemia","volume":"69","author":"Pigazzi","year":"2009","journal-title":"Cancer Res."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"602","DOI":"10.3324\/haematol.2012.070664","article-title":"MicroRNA-34b promoter hypermethylation induces CREB overexpression and contributes to myeloid transformation","volume":"98","author":"Pigazzi","year":"2013","journal-title":"Haematologica"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1111\/j.1365-2141.2011.08782.x","article-title":"Epigenetic silencing of MIR203 in multiple myeloma","volume":"154","author":"Wong","year":"2011","journal-title":"Br. J. Haematol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"4196","DOI":"10.7150\/jca.58522","article-title":"MicroRNA-1246 by Targeting AXIN2 and GSK-3\u03b2 Overcomes Drug Resistance and Induces Apoptosis in Chemo-resistant Leukemia Cells","volume":"12","author":"Xie","year":"2021","journal-title":"J. Cancer"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1089\/ars.2013.5648","article-title":"MicroRNA target identification: Lessons from hypoxamiRs","volume":"21","author":"Bertero","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"11452","DOI":"10.1038\/ncomms11452","article-title":"MiR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia","volume":"7","author":"Jiang","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Ahmed, M.B., Alghamdi, A.A.A., Islam, S.U., Lee, J.-S., and Lee, Y.-S. (2022). cAMP Signaling in Cancer: A PKA-CREB and EPAC-Centric Approach. Cells, 11.","DOI":"10.3390\/cells11132020"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s12014-022-09385-7","article-title":"Phospho-heavy-labeled-spiketide FAIMS stepped-CV DDA (pHASED) provides real-time phosphoproteomics data to aid in cancer drug selection","volume":"19","author":"Staudt","year":"2022","journal-title":"Clin. Proteom."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1038\/leu.2014.123","article-title":"Feedbacks and adaptive capabilities of the PI3K\/Akt\/mTOR axis in acute myeloid leukemia revealed by pathway selective inhibition and phosphoproteome analysis","volume":"28","author":"Bertacchini","year":"2014","journal-title":"Leukemia"},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Nepstad, I., Hatfield, K.J., Gr\u00f8nnings\u00e6ter, I.S., and Reikvam, H. (2020). The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082907"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"5765","DOI":"10.1182\/blood-2023-187063","article-title":"Targeting CREB-Binding Protein (CREBBP) Overcomes Resistance to Azacitidine and Venetoclax Therapy in Acute Myeloid Leukemia (AML)","volume":"142","author":"LeBlanc","year":"2023","journal-title":"Blood"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"5755","DOI":"10.18632\/oncotarget.27206","article-title":"PTEN deletion drives acute myeloid leukemia resistance to MEK inhibitors","volume":"10","author":"Smith","year":"2019","journal-title":"Oncotarget"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8300\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:22:06Z","timestamp":1790860926000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8300"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,17]]},"references-count":139,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27188300"],"URL":"https:\/\/doi.org\/10.3390\/ijms27188300","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,17]]}}}