{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:05:21Z","timestamp":1787162721288,"version":"build-2736575974"},"reference-count":40,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T00:00:00Z","timestamp":1670889600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Precious Jules Foundation Childhood Cancer Research Award","award":["HHSN261200800001E"],"award-info":[{"award-number":["HHSN261200800001E"]}]},{"name":"Emily Beazley Kures for Kids St. Baldrick\u2019s Foundation Fellowship","award":["HHSN261200800001E"],"award-info":[{"award-number":["HHSN261200800001E"]}]},{"name":"CURE Childhood Cancer Research Fellowship","award":["HHSN261200800001E"],"award-info":[{"award-number":["HHSN261200800001E"]}]},{"name":"CURE Childhood Cancer Sam Robb Research Fellowship","award":["HHSN261200800001E"],"award-info":[{"award-number":["HHSN261200800001E"]}]},{"name":"National Cancer Institute Experimental Therapeutics (NExT) Program, National Institutes of Health","award":["HHSN261200800001E"],"award-info":[{"award-number":["HHSN261200800001E"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of childhood ALL. The early T-precursor (ETP-ALL) subset is characterized by an immature T-cell phenotype, chemoresistance, and high rates of induction failure. MERTK receptor tyrosine kinase is ectopically expressed in half of T-ALLs, particularly those with an immature T-cell phenotype, suggesting a role in ETP-ALL. The anti-apoptotic protein B-cell lymphoma-2 (BCL-2) is essential for ETP-ALL cell survival. Here, we show that MERTK and BCL-2 mRNA and protein are preferentially expressed in ETP-ALL patient samples. The dual MERTK\/FLT3 inhibitor MRX-2843 decreased MERTK activation and downstream signaling, inhibited cell expansion, and induced cell death in ETP-ALL cell lines. Further, 54% (21\/39) of primary T-ALL patient samples were sensitive to MERTK inhibition. Treatment with MRX-2843 significantly reduced leukemia burden and prolonged survival in cell-line-derived T-ALL and ETP-ALL xenograft models. In a patient-derived ETP-ALL xenograft model, treatment with MRX-2843 markedly reduced peripheral blood leukemia and spleen weight compared to vehicle-treated mice and prolonged survival. MRX-2843 also synergized with venetoclax to provide enhanced anti-leukemia activity in ETP-ALL cell cultures, with a dose ratio of 1:20 MRX-2843:venetoclax providing optimal synergy. These data demonstrate the therapeutic potential of MRX-2843 in patients with T-ALL and provide rationale for clinical development. MRX-2843 monotherapy is currently being tested in patients with relapsed leukemia (NCT04872478). Further, our data indicate that combined MERTK and BCL-2 inhibition may be particularly effective for treatment of ETP-ALL.<\/jats:p>","DOI":"10.3390\/cancers14246142","type":"journal-article","created":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T04:32:48Z","timestamp":1670905968000},"page":"6142","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Therapeutic Targeting of MERTK and BCL-2 in T-Cell and Early T-Precursor Acute Lymphoblastic Leukemia"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3621-8664","authenticated-orcid":false,"given":"Ryan J.","family":"Summers","sequence":"first","affiliation":[{"name":"Aflac Cancer & Blood Disorders Center, Children\u2019s Healthcare of Atlanta and Emory University, Atlanta, GA 30322, USA"},{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juhi","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Arizona School of Medicine, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleana","family":"Vasileiadi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany","family":"Smith","sequence":"additional","affiliation":[{"name":"School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison L.","family":"Chimenti","sequence":"additional","affiliation":[{"name":"Aflac Cancer & Blood Disorders Center, Children\u2019s Healthcare of Atlanta and Emory University, Atlanta, GA 30322, USA"},{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsz Y.","family":"Yeung","sequence":"additional","affiliation":[{"name":"Aflac Cancer & Blood Disorders Center, Children\u2019s Healthcare of Atlanta and Emory University, Atlanta, GA 30322, USA"},{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Kelvin","sequence":"additional","affiliation":[{"name":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2415-2215","authenticated-orcid":false,"given":"Stephen V.","family":"Frye","sequence":"additional","affiliation":[{"name":"Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Shelton","family":"Earp","sequence":"additional","affiliation":[{"name":"UNC Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey W.","family":"Tyner","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health Sciences University, Portland, OR 97201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik C.","family":"Dreaden","sequence":"additional","affiliation":[{"name":"Aflac Cancer & Blood Disorders Center, Children\u2019s Healthcare of Atlanta and Emory University, Atlanta, GA 30322, USA"},{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7457-9006","authenticated-orcid":false,"given":"Deborah","family":"DeRyckere","sequence":"additional","affiliation":[{"name":"Aflac Cancer & Blood Disorders Center, Children\u2019s Healthcare of Atlanta and Emory University, Atlanta, GA 30322, USA"},{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas K.","family":"Graham","sequence":"additional","affiliation":[{"name":"Aflac Cancer & Blood Disorders Center, Children\u2019s Healthcare of Atlanta and Emory University, Atlanta, GA 30322, USA"},{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3282","DOI":"10.1200\/JCO.20.00256","article-title":"Children\u2019s Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia","volume":"38","author":"Dunsmore","year":"2020","journal-title":"J. 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