{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T03:33:16Z","timestamp":1791343996571,"version":"4.3.1"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2016,2,12]],"date-time":"2016-02-12T00:00:00Z","timestamp":1455235200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2016,2,12]],"date-time":"2016-02-12T00:00:00Z","timestamp":1455235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2016,6]]},"DOI":"10.1038\/leu.2016.14","type":"journal-article","created":{"date-parts":[[2016,3,11]],"date-time":"2016-03-11T09:52:05Z","timestamp":1457689925000},"page":"1335-1343","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Targeting the PI3K\/Akt pathway in murine MDS\/MPN driven by hyperactive Ras"],"prefix":"10.1038","volume":"30","author":[{"given":"J","family":"Akutagawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T Q","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I","family":"Epstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Quirindongo-Crespo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C L","family":"Cottonham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Dail","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B S","family":"Slusher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L S","family":"Friedman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Sampath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B S","family":"Braun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,2,12]]},"reference":[{"key":"BFleu201614_CR1","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1038\/leu.2008.162","volume":"22","author":"PD Emanuel","year":"2008","unstructured":"Emanuel PD . Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. Leukemia 2008; 22: 1335\u20131342.","journal-title":"Leukemia"},{"key":"BFleu201614_CR2","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1111\/j.1365-2141.2011.08631.x","volume":"153","author":"U Bacher","year":"2011","unstructured":"Bacher U, Haferlach T, Schnittger S, Kreipe H, Kroger N . Recent advances in diagnosis, molecular pathology and therapy of chronic myelomonocytic leukaemia. Br J Haematol 2011; 153: 149\u2013167.","journal-title":"Br J Haematol"},{"key":"BFleu201614_CR3","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1182\/blood-2004-05-1944","volume":"105","author":"F Locatelli","year":"2005","unstructured":"Locatelli F, Nollke P, Zecca M, Korthof E, Lanino E, Peters C et al. Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS\/EBMT trial. Blood 2005; 105: 410\u2013419.","journal-title":"Blood"},{"key":"BFleu201614_CR4","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1111\/j.1365-2141.2010.08525.x","volume":"152","author":"ML Loh","year":"2011","unstructured":"Loh ML . Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J Haematol 2011; 152: 677\u2013687.","journal-title":"Br J Haematol"},{"key":"BFleu201614_CR5","doi-asserted-by":"publisher","first-page":"3858","DOI":"10.1200\/JCO.2009.27.1361","volume":"28","author":"A Kohlmann","year":"2010","unstructured":"Kohlmann A, Grossmann V, Klein HU, Schindela S, Weiss T, Kazak B et al. Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1. J Clin Oncol 2010; 28: 3858\u20133865.","journal-title":"J Clin Oncol"},{"key":"BFleu201614_CR6","doi-asserted-by":"publisher","first-page":"3397","DOI":"10.1182\/blood-2012-05-378596","volume":"120","author":"AF Ward","year":"2012","unstructured":"Ward AF, Braun BS, Shannon KM . Targeting oncogenic Ras signaling in hematologic malignancies. Blood 2012; 120: 3397\u20133406.","journal-title":"Blood"},{"key":"BFleu201614_CR7","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/nrc969","volume":"3","author":"J Downward","year":"2003","unstructured":"Downward J . Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003; 3: 11\u201322.","journal-title":"Nat Rev Cancer"},{"key":"BFleu201614_CR8","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1038\/nrc839","volume":"2","author":"I Vivanco","year":"2002","unstructured":"Vivanco I, Sawyers CL . The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2: 489\u2013501.","journal-title":"Nat Rev Cancer"},{"key":"BFleu201614_CR9","doi-asserted-by":"publisher","first-page":"ra105","DOI":"10.1126\/scisignal.2004125","volume":"6","author":"E Diaz-Flores","year":"2013","unstructured":"Diaz-Flores E, Goldschmidt H, Depeille P, Ng V, Akutagawa J, Krisman K et al. PLC-\u03b3 and PI3K link cytokines to ERK activation in hematopoietic cells with normal and oncogenic Kras. Sci Signal 2013; 6: ra105.","journal-title":"Sci Signal"},{"key":"BFleu201614_CR10","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1073\/pnas.0307203101","volume":"101","author":"BS Braun","year":"2004","unstructured":"Braun BS, Tuveson DA, Kong N, Le DT, Kogan SC, Rozmus J et al. Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc Natl Acad Sci USA 2004; 101: 597\u2013602.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFleu201614_CR11","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1172\/JCI20476","volume":"113","author":"IT Chan","year":"2004","unstructured":"Chan IT, Kutok JL, Williams IR, Cohen S, Kelly L, Shigematsu H et al. Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease. J Clin Invest 2004; 113: 528\u2013538.","journal-title":"J Clin Invest"},{"key":"BFleu201614_CR12","doi-asserted-by":"publisher","first-page":"e59","DOI":"10.1371\/journal.pbio.1000059","volume":"7","author":"AJ Sabnis","year":"2009","unstructured":"Sabnis AJ, Cheung LS, Dail M, Kang HC, Santaguida M, Hermiston ML et al. Oncogenic Kras initiates leukemia in hematopoietic stem cells. PLoS Biol 2009; 7: e59.","journal-title":"PLoS Biol"},{"key":"BFleu201614_CR13","doi-asserted-by":"publisher","first-page":"76ra27","DOI":"10.1126\/scitranslmed.3001069","volume":"3","author":"N Lyubynska","year":"2011","unstructured":"Lyubynska N, Gorman MF, Lauchle JO, Hong WX, Akutagawa JK, Shannon K et al. A MEK inhibitor abrogates myeloproliferative disease in Kras mutant mice. Sci Transl Med 2011; 3: 76ra27.","journal-title":"Sci Transl Med"},{"key":"BFleu201614_CR14","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1172\/JCI63193","volume":"123","author":"T Chang","year":"2013","unstructured":"Chang T, Krisman K, Theobald EH, Xu J, Akutagawa J, Lauchle JO et al. Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J Clin Invest 2013; 123: 335\u2013339.","journal-title":"J Clin Invest"},{"key":"BFleu201614_CR15","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/j.leukres.2008.09.036","volume":"33","author":"YL Liu","year":"2009","unstructured":"Liu YL, Castleberry RP, Emanuel PD . PTEN deficiency is a common defect in juvenile myelomonocytic leukemia. Leuk Res 2009; 33: 671\u2013677.","journal-title":"Leuk Res"},{"key":"BFleu201614_CR16","doi-asserted-by":"publisher","first-page":"2838","DOI":"10.1182\/blood-2013-10-535104","volume":"123","author":"CB Goodwin","year":"2014","unstructured":"Goodwin CB, Li XJ, Mali RS, Chan G, Kang M, Liu Z et al. PI3K p110\u03b4 uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML. Blood 2014; 123: 2838\u20132842.","journal-title":"Blood"},{"key":"BFleu201614_CR17","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.1172\/JCI69927","volume":"124","author":"K Gritsman","year":"2014","unstructured":"Gritsman K, Yuzugullu H, Von T, Yan H, Clayton L, Fritsch C et al. Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110\u03b1. J Clin Invest 2014; 124: 1794\u20131809.","journal-title":"J Clin Invest"},{"issue":"9 Suppl","key":"BFleu201614_CR18","first-page":"DDT01-01","volume":"69","author":"L Yan","year":"2009","unstructured":"Yan L . Abstract #DDT01-1: MK-2206: a potent oral allosteric AKT inhibitor. Cancer Res 2009; 69 (9 Suppl): DDT01-01.","journal-title":"Cancer Res"},{"key":"BFleu201614_CR19","doi-asserted-by":"publisher","first-page":"3945","DOI":"10.1182\/blood-2006-09-047530","volume":"109","author":"ME Van Meter","year":"2007","unstructured":"Van Meter ME, Diaz-Flores E, Archard JA, Passegue E, Irish JM, Kotecha N et al. K-RasG12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem\/progenitor cells. Blood 2007; 109: 3945\u20133952.","journal-title":"Blood"},{"key":"BFleu201614_CR20","unstructured":"Core Team. R, R. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing: Vienna, Austria, 2014."},{"key":"BFleu201614_CR21","doi-asserted-by":"publisher","first-page":"5522","DOI":"10.1021\/jm800295d","volume":"51","author":"A Folkes","year":"2008","unstructured":"Folkes A, Ahmadi K, Alderton W, Alix S, Baker S, Box G et al. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem 2008; 51: 5522\u20135532.","journal-title":"J Med Chem"},{"key":"BFleu201614_CR22","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.1158\/1535-7163.MCT-08-1200","volume":"8","author":"FI Raynaud","year":"2009","unstructured":"Raynaud FI, Eccles SA, Patel S, Alix S, Box G, Chuckowree I et al. Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941. Mol Cancer Ther 2009; 8: 1725\u20131738.","journal-title":"Mol Cancer Ther"},{"key":"BFleu201614_CR23","doi-asserted-by":"publisher","first-page":"3670","DOI":"10.1158\/1078-0432.CCR-09-2828","volume":"16","author":"C O'Brien","year":"2010","unstructured":"O'Brien C, Wallin JJ, Sampath D, GuhaThakurta D, Savage H, Punnoose EA et al. Predictive biomarkers of sensitivity to the phosphatidylinositol 3\u2032 kinase inhibitor. GDC-0941 in breast cancer preclinical models. Clin Cancer Res 2010; 16: 3670\u20133683.","journal-title":"Clin Cancer Res"},{"key":"BFleu201614_CR24","doi-asserted-by":"publisher","first-page":"3901","DOI":"10.1158\/1078-0432.CCR-11-2088","volume":"18","author":"JJ Wallin","year":"2012","unstructured":"Wallin JJ, Guan J, Prior WW, Lee LB, Berry L, Belmont LD et al. GDC-0941, a novel class I selective PI3K inhibitor, enhances the efficacy of docetaxel in human breast cancer models by increasing cell death in vitro and in vivo. Clin Cancer Res 2012; 18: 3901\u20133911.","journal-title":"Clin Cancer Res"},{"key":"BFleu201614_CR25","doi-asserted-by":"publisher","first-page":"6771","DOI":"10.1158\/1078-0432.CCR-12-2347","volume":"18","author":"JM Spoerke","year":"2012","unstructured":"Spoerke JM, O'Brien C, Huw L, Koeppen H, Fridlyand J, Brachmann RK et al. Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models. Clin Cancer Res 2012; 18: 6771\u20136783.","journal-title":"Clin Cancer Res"},{"key":"BFleu201614_CR26","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1038\/nature13495","volume":"513","author":"M Dail","year":"2014","unstructured":"Dail M, Wong J, Lawrence J, O'Connor D, Nakitandwe J, Chen SC et al. Loss of oncogenic Notch1 with resistance to a PI3K inhibitor in T-cell leukaemia. Nature 2014; 513: 512\u2013516.","journal-title":"Nature"},{"key":"BFleu201614_CR27","doi-asserted-by":"publisher","first-page":"2041","DOI":"10.1182\/blood-2006-01-013490","volume":"108","author":"BS Braun","year":"2006","unstructured":"Braun BS, Archard JA, Van Ziffle JA, Tuveson DA, Jacks TE, Shannon K . Somatic activation of a conditional KrasG12D allele causes ineffective erythropoiesis in vivo. Blood 2006; 108: 2041\u20132044.","journal-title":"Blood"},{"key":"BFleu201614_CR28","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1016\/j.stem.2007.07.005","volume":"1","author":"CJ Pronk","year":"2007","unstructured":"Pronk CJ, Rossi DJ, Mansson R, Attema JL, Norddahl GL, Chan CK et al. Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy. Cell Stem Cell 2007; 1: 428\u2013442.","journal-title":"Cell Stem Cell"},{"key":"BFleu201614_CR29","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/nrm2882","volume":"11","author":"B Vanhaesebroeck","year":"2010","unstructured":"Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B . The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol 2010; 11: 329\u2013341.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"BFleu201614_CR30","doi-asserted-by":"publisher","first-page":"e12913","DOI":"10.1371\/journal.pone.0012913","volume":"5","author":"WI Wu","year":"2010","unstructured":"Wu WI, Voegtli WC, Sturgis HL, Dizon FP, Vigers GP, Brandhuber BJ . Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition. PLoS One 2010; 5: e12913.","journal-title":"PLoS One"},{"key":"BFleu201614_CR31","doi-asserted-by":"publisher","first-page":"e109705","DOI":"10.1371\/journal.pone.0109705","volume":"9","author":"M Rehan","year":"2014","unstructured":"Rehan M, Beg MA, Parveen S, Damanhouri GA, Zaher GF . Computational insights into the inhibitory mechanism of human AKT1 by an orally active inhibitor, MK-2206. PLoS One 2014; 9: e109705.","journal-title":"PLoS One"},{"key":"BFleu201614_CR32","doi-asserted-by":"publisher","first-page":"4243","DOI":"10.1182\/blood-2003-08-2650","volume":"103","author":"DT Le","year":"2004","unstructured":"Le DT, Kong N, Zhu Y, Lauchle JO, Aiyigari A, Braun BS et al. Somatic inactivation of Nf1 in hematopoietic cells results in a progressive myeloproliferative disorder. Blood 2004; 103: 4243\u20134250.","journal-title":"Blood"},{"key":"BFleu201614_CR33","doi-asserted-by":"publisher","first-page":"2701","DOI":"10.1038\/sj.onc.1202201","volume":"17","author":"T Matsuguchi","year":"1998","unstructured":"Matsuguchi T, Kraft AS . Regulation of myeloid cell growth by distinct effectors of Ras. Oncogene 1998; 17: 2701\u20132709.","journal-title":"Oncogene"},{"key":"BFleu201614_CR34","doi-asserted-by":"publisher","first-page":"4884","DOI":"10.1182\/blood-2012-05-432252","volume":"121","author":"A Shieh","year":"2013","unstructured":"Shieh A, Ward AF, Donlan KL, Harding-Theobald ER, Xu J, Mullighan CG et al. Defective K-Ras oncoproteins overcome impaired effector activation to initiate leukemia in vivo. Blood 2013; 121: 4884\u20134893.","journal-title":"Blood"},{"key":"BFleu201614_CR35","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1038\/leu.2014.315","volume":"29","author":"A Staffas","year":"2015","unstructured":"Staffas A, Karlsson C, Persson M, Palmqvist L, Bergo MO . Wild-type KRAS inhibits oncogenic KRAS-induced T-ALL in mice. Leukemia 2015; 29: 1032\u20131040.","journal-title":"Leukemia"},{"key":"BFleu201614_CR36","doi-asserted-by":"publisher","first-page":"3938","DOI":"10.1182\/blood-2003-05-1479","volume":"102","author":"J Zhang","year":"2003","unstructured":"Zhang J, Socolovsky M, Gross AW, Lodish HF . Role of Ras signaling in erythroid differentiation of mouse fetal liver cells: functional analysis by a flow cytometry-based novel culture system. Blood 2003; 102: 3938\u20133946.","journal-title":"Blood"},{"key":"BFleu201614_CR37","doi-asserted-by":"publisher","first-page":"1679","DOI":"10.1182\/blood-2004-04-1362","volume":"104","author":"J Zhang","year":"2004","unstructured":"Zhang J, Lodish HF . Constitutive activation of the MEK\/ERK pathway mediates all effects of oncogenic H-ras expression in primary erythroid progenitors. Blood 2004; 104: 1679\u20131687.","journal-title":"Blood"},{"key":"BFleu201614_CR38","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1038\/leu.2012.316","volume":"27","author":"P Tang","year":"2013","unstructured":"Tang P, Gao C, Li A, Aster J, Sun L, Chai L . Differential roles of Kras and Pten in murine leukemogenesis. Leukemia 2013; 27: 1210\u20131214.","journal-title":"Leukemia"},{"key":"BFleu201614_CR39","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1016\/j.bbamcr.2010.04.005","volume":"1803","author":"AM Martelli","year":"2010","unstructured":"Martelli AM, Evangelisti C, Chiarini F, Grimaldi C, Cappellini A, Ognibene A et al. The emerging role of the phosphatidylinositol 3-kinase\/Akt\/mammalian target of rapamycin signaling network in normal myelopoiesis and leukemogenesis. Biochim Biophys Acta 2010; 1803: 991\u20131002.","journal-title":"Biochim Biophys Acta"},{"key":"BFleu201614_CR40","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/sj.gene.6364042","volume":"5","author":"CM Elso","year":"2004","unstructured":"Elso CM, Roberts LJ, Smyth GK, Thomson RJ, Baldwin TM, Foote SJ et al. Leishmaniasis host response loci (lmr1-3) modify disease severity through a Th1\/Th2-independent pathway. Genes Immun 2004; 5: 93\u2013100.","journal-title":"Genes Immun"},{"key":"BFleu201614_CR41","unstructured":"Smyth G, Thompson R, Satterley K . Available at: http:\/\/bioinf.wehi.edu.au\/software\/compareCurves\/ (last accessed 17 December 2013)."}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/leu201614.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/leu201614","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/leu201614.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,31]],"date-time":"2022-03-31T16:19:56Z","timestamp":1648743596000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/leu201614"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,2,12]]},"references-count":41,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2016,6]]}},"alternative-id":["BFleu201614"],"URL":"https:\/\/doi.org\/10.1038\/leu.2016.14","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,2,12]]},"assertion":[{"value":"22 September 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 December 2015","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 January 2016","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 February 2016","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"DS and LF are employed by Genentech; MD and TC are currently employed by Genentech, but were not when contributing to this work.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}