Leukemia Program

The DF/HCC Leukemia Program conducts innovative translational research to improve the therapy of leukemia and related disorders, with a focus on discoveries that will lead to improvements in diagnosis, prognosis, and therapy. To harness the power of interdisciplinary translational science, the program brings together 70 investigators representing multiple DF/HCC institutions, departments, and disciplines.

Program members have expertise in identifying oncogenes, defining basic mechanisms of neoplastic transformation in cell culture and murine models of leukemia, analyzing the biology of myeloproliferative neoplasms, developing novel immunotherapeutic approaches, conducting clinical trials of novel therapies, and investigating outcomes for stem cell transplantation as therapy of leukemia. Program publications represent landmark advances that have improved the understanding of leukemia pathobiology and translated gains into improved therapies.

Recent Publications

  • Chung J, Bauer DE, Ghamari A, Nizzi CP, Deck KM, Kingsley PD, Yien YY, Huston NC, Chen C, Schultz IJ, Dalton AJ, Wittig JG, Palis J, Orkin SH, Lodish HF, Eisenstein RS, Cantor AB, Paw BH. The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability. Sci Signal 2015; 8:ra34. PubMed
  • Montero J, Sarosiek KA, DeAngelo JD, Maertens O, Ryan J, Ercan D, Piao H, Horowitz NS, Berkowitz RS, Matulonis U, Jänne PA, Amrein PC, Cichowski K, Drapkin R, Letai A. Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. Cell 2015; 160:977-89. PubMed
  • Xu J, Shao Z, Li D, Xie H, Kim W, Huang J, Taylor JE, Pinello L, Glass K, Jaffe JD, Yuan GC, Orkin SH. Developmental control of polycomb subunit composition by GATA factors mediates a switch to non-canonical functions. Mol Cell 2015; 57:304-16. PubMed
  • Tamplin OJ, Durand EM, Carr LA, Childs SJ, Hagedorn EJ, Li P, Yzaguirre AD, Speck NA, Zon LI. Hematopoietic stem cell arrival triggers dynamic remodeling of the perivascular niche. Cell 2015; 160:241-52. PubMed
  • Yoda A, Adelmant G, Tamburini J, Chapuy B, Shindoh N, Yoda Y, Weigert O, Kopp N, Wu SC, Kim SS, Liu H, Tivey T, Christie AL, Elpek KG, Card J, Gritsman K, Gotlib J, Deininger MW, Makishima H, Turley SJ, Javidi-Sharifi N, Maciejewski JP, Jaiswal S, Ebert BL, Rodig SJ, Tyner JW, Marto JA, Weinstock DM, Lane AA. Mutations in G protein 硫 subunits promote transformation and kinase inhibitor resistance. Nat Med 2015; 21:71-5. PubMed
  • Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, Lindsley RC, Mermel CH, Burtt N, Chavez A, Higgins JM, Moltchanov V, Kuo FC, Kluk MJ, Henderson B, Kinnunen L, Koistinen HA, Ladenvall C, Getz G, Correa A, Banahan BF, Gabriel S, Kathiresan S, Stringham HM, McCarthy MI, Boehnke M, Tuomilehto J, Haiman C, Groop L, Atzmon G, Wilson JG, Neuberg D, Altshuler D, Ebert BL. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014; 371:2488-98. PubMed
  • Mansour MR, Abraham BJ, Anders L, Berezovskaya A, Gutierrez A, Durbin AD, Etchin J, Lawton L, Sallan SE, Silverman LB, Loh ML, Hunger SP, Sanda T, Young RA, Look AT. Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 2014; 346:1373-7. PubMed
  • Lee D, Sykes SM, Kalaitzidis D, Lane AA, Kfoury Y, Raaijmakers MH, Wang YH, Armstrong SA, Scadden DT. Transmembrane Inhibitor of RICTOR/mTORC2 in Hematopoietic Progenitors. Stem Cell Reports 2014; 3:832-40. PubMed
  • Li N, Fassl A, Chick J, Inuzuka H, Li X, Mansour MR, Liu L, Wang H, King B, Shaik S, Gutierrez A, Ordureau A, Otto T, Kreslavsky T, Baitsch L, Bury L, Meyer CA, Ke N, Mulry KA, Kluk MJ, Roy M, Kim S, Zhang X, Geng Y, Zagozdzon A, Jenkinson S, Gale RE, Linch DC, Zhao JJ, Mullighan CG, Harper JW, Aster JC, Aifantis I, von Boehmer H, Gygi SP, Wei W, Look AT, Sicinski P. Cyclin C is a haploinsufficient tumour suppressor. Nat Cell Biol 2014; 16:1080-91. PubMed
  • Schneider RK, Ademà V, Heckl D, Järås M, Mallo M, Lord AM, Chu LP, McConkey ME, Kramann R, Mullally A, Bejar R, Solé F, Ebert BL. Role of Casein Kinase 1A1 in the Biology and Targeted Therapy of del(5q) MDS. Cancer Cell 2014; 26:509-20. PubMed
  • Wang YH, Israelsen WJ, Lee D, Yu VW, Jeanson NT, Clish CB, Cantley LC, Vander Heiden MG, Scadden DT. Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis. Cell 2014; 158:1309-23. PubMed
  • Heckl D, Kowalczyk MS, Yudovich D, Belizaire R, Puram RV, McConkey ME, Thielke A, Aster JC, Regev A, Ebert BL. Generation of mouse models of myeloid malignancy with combinatorial genetic lesions using CRISPR-Cas9 genome editing. Nat Biotechnol 2014; 32:941-6. PubMed
  • Morris SA, Cahan P, Li H, Zhao AM, San Roman AK, Shivdasani RA, Collins JJ, Daley GQ. Dissecting engineered cell types and enhancing cell fate conversion via CellNet. Cell 2014; 158:889-902. PubMed
  • Choi YJ, Saez B, Anders L, Hydbring P, Stefano J, Bacon NA, Cook C, Kalaszczynska I, Signoretti S, Young RA, Scadden DT, Sicinski P. D-cyclins repress apoptosis in hematopoietic cells by controlling death receptor Fas and its ligand FasL. Dev Cell 2014; 30:255-67. PubMed
  • Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB, Dastur A, Amzallag A, Ramaswamy S, Tesar B, Jenkins CE, Hannett NM, McMillin D, Sanda T, Sim T, Kim ND, Look T, Mitsiades CS, Weng AP, Brown JR, Benes CH, Marto JA, Young RA, Gray NS. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 2014. PubMed
  • Tang Q, Abdelfattah NS, Blackburn JS, Moore JC, Martinez SA, Moore FE, Lobbardi R, Tenente IM, Ignatius MS, Berman JN, Liwski RS, Houvras Y, Langenau DM. Optimized cell transplantation using adult rag2 mutant zebrafish. Nat Methods 2014. PubMed
  • Arora N, Wenzel PL, McKinney-Freeman SL, Ross SJ, Kim PG, Chou SS, Yoshimoto M, Yoder MC, Daley GQ. Effect of Developmental Stage of HSC and Recipient on Transplant Outcomes. Dev Cell 2014; 29:621-8. PubMed
  • Carroll KJ, Esain V, Garnaas MK, Cortes M, Dovey MC, Nissim S, Frechette GM, Liu SY, Kwan W, Cutting CC, Harris JM, Gorelick DA, Halpern ME, Lawson ND, Goessling W, North TE. Estrogen defines the dorsal-ventral limit of VEGF regulation to specify the location of the hemogenic endothelial niche. Dev Cell 2014; 29:437-53. PubMed
  • Lane AA, Chapuy B, Lin CY, Tivey T, Li H, Townsend EC, van Bodegom D, Day TA, Wu SC, Liu H, Yoda A, Alexe G, Schinzel AC, Sullivan TJ, Malinge S, Taylor JE, Stegmaier K, Jaffe JD, Bustin M, te Kronnie G, Izraeli S, Harris MH, Stevenson KE, Neuberg D, Silverman LB, Sallan SE, Bradner JE, Hahn WC, Crispino JD, Pellman D, Weinstock DM. Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation. Nat Genet 2014. PubMed
  • Papa A, Wan L, Bonora M, Salmena L, Song MS, Hobbs RM, Lunardi A, Webster K, Ng C, Newton RH, Knoblauch N, Guarnerio J, Ito K, Turka LA, Beck AH, Pinton P, Bronson RT, Wei W, Pandolfi PP. Cancer-Associated PTEN Mutants Act in a Dominant-Negative Manner to Suppress PTEN Protein Function. Cell 2014; 157:595-610. PubMed
  • Spencer JA, Ferraro F, Roussakis E, Klein A, Wu J, Runnels JM, Zaher W, Mortensen LJ, Alt C, Turcotte R, Yusuf R, Côté D, Vinogradov SA, Scadden DT, Lin CP. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 2014; 508:269-73. PubMed
  • Van Agthoven JF, Xiong JP, Alonso JL, Rui X, Adair BD, Goodman SL, Arnaout MA. Structural basis for pure antagonism of integrin 留V硫3 by a high-affinity form of fibronectin. Nat Struct Mol Biol 2014; 21:383-8. PubMed
  • Knoechel B, Roderick JE, Williamson KE, Zhu J, Lohr JG, Cotton MJ, Gillespie SM, Fernandez D, Ku M, Wang H, Piccioni F, Silver SJ, Jain M, Pearson D, Kluk MJ, Ott CJ, Shultz LD, Brehm MA, Greiner DL, Gutierrez A, Stegmaier K, Kung AL, Root DE, Bradner JE, Aster JC, Kelliher MA, Bernstein BE. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat Genet 2014; 46:364-70. PubMed
  • Blackburn JS, Liu S, Wilder JL, Dobrinski KP, Lobbardi R, Moore FE, Martinez SA, Chen EY, Lee C, Langenau DM. Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation. Cancer Cell 2014; 25:366-78. PubMed
  • Kats LM, Reschke M, Taulli R, Pozdnyakova O, Burgess K, Bhargava P, Straley K, Karnik R, Meissner A, Small D, Su SM, Yen K, Zhang J, Pandolfi PP. Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance. Cell Stem Cell 2014; 14:329-41. PubMed
  • Puissant A, Fenouille N, Alexe G, Pikman Y, Bassil CF, Mehta S, Du J, Kazi JU, Luciano F, Rönnstrand L, Kung AL, Aster JC, Galinsky I, Stone RM, DeAngelo DJ, Hemann MT, Stegmaier K. SYK is a critical regulator of FLT3 in acute myeloid leukemia. Cancer Cell 2014; 25:226-42. PubMed
  • Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X, Ciarlo C, Hartman E, Munshi N, Schenone M, Schreiber SL, Carr SA, Ebert BL. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 2014; 343:301-5. PubMed
  • Das PP, Shao Z, Beyaz S, Apostolou E, Pinello L, De Los Angeles A, O'Brien K, Atsma JM, Fujiwara Y, Nguyen M, Ljuboja D, Guo G, Woo A, Yuan GC, Onder T, Daley G, Hochedlinger K, Kim J, Orkin SH. Distinct and combinatorial functions of Jmjd2b/Kdm4b and Jmjd2c/Kdm4c in mouse embryonic stem cell identity. Mol Cell 2014; 53:32-48. PubMed
  • Xie H, Xu J, Hsu JH, Nguyen M, Fujiwara Y, Peng C, Orkin SH. Polycomb repressive complex 2 regulates normal hematopoietic stem cell function in a developmental-stage-specific manner. Cell Stem Cell 2014; 14:68-80. PubMed
  • Catic A, Suh CY, Hill CT, Daheron L, Henkel T, Orford KW, Dombkowski DM, Liu T, Liu XS, Scadden DT. Genome-wide map of nuclear protein degradation shows NCoR1 turnover as a key to mitochondrial gene regulation. Cell 2013; 155:1380-95. PubMed
  • Huang HT, Kathrein KL, Barton A, Gitlin Z, Huang YH, Ward TP, Hofmann O, Dibiase A, Song A, Tyekucheva S, Hide W, Zhou Y, Zon LI. A network of epigenetic regulators guides developmental haematopoiesis in vivo. Nat Cell Biol 2013; 15:1516-25. PubMed
  • Paik EJ, Mahony S, White RM, Price EN, Dibiase A, Dorjsuren B, Mosimann C, Davidson AJ, Gifford D, Zon LI. A cdx4-sall4 regulatory module controls the transition from mesoderm formation to embryonic hematopoiesis. Stem Cell Reports 2013; 1:425-36. PubMed
  • Di Ruscio A, Ebralidze AK, Benoukraf T, Amabile G, Goff LA, Terragni J, Figueroa ME, De Figueiredo Pontes LL, Alberich-Jorda M, Zhang P, Wu M, D'Alò F, Melnick A, Leone G, Ebralidze KK, Pradhan S, Rinn JL, Tenen DG. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature 2013; 503:371-6. PubMed
  • Hartwell KA, Miller PG, Mukherjee S, Kahn AR, Stewart AL, Logan DJ, Negri JM, Duvet M, Järås M, Puram R, Dancik V, Al-Shahrour F, Kindler T, Tothova Z, Chattopadhyay S, Hasaka T, Narayan R, Dai M, Huang C, Shterental S, Chu LP, Haydu JE, Shieh JH, Steensma DP, Munoz B, Bittker JA, Shamji AF, Clemons PA, Tolliday NJ, Carpenter AE, Gilliland DG, Stern AM, Moore MA, Scadden DT, Schreiber SL, Ebert BL, Golub TR. Niche-based screening identifies small-molecule inhibitors of leukemia stem cells. Nat Chem Biol 2013; 9:840-8. PubMed
  • Zhang H, Alberich-Jorda M, Amabile G, Yang H, Staber PB, Di Ruscio A, Diruscio A, Welner RS, Ebralidze A, Zhang J, Levantini E, Lefebvre V, Valk PJ, Delwel R, Hoogenkamp M, Nerlov C, Cammenga J, Saez B, Scadden DT, Bonifer C, Ye M, Tenen DG. Sox4 is a key oncogenic target in C/EBP留 mutant acute myeloid leukemia. Cancer Cell 2013; 24:575-88. PubMed
  • Krause DS, Fulzele K, Catic A, Sun CC, Dombkowski D, Hurley MP, Lezeau S, Attar E, Wu JY, Lin HY, Divieti-Pajevic P, Hasserjian RP, Schipani E, Van Etten RA, Scadden DT. Differential regulation of myeloid leukemias by the bone marrow microenvironment. Nat Med 2013; 19:1513-7. PubMed
  • Bauer DE, Kamran SC, Lessard S, Xu J, Fujiwara Y, Lin C, Shao Z, Canver MC, Smith EC, Pinello L, Sabo PJ, Vierstra J, Voit RA, Yuan GC, Porteus MH, Stamatoyannopoulos JA, Lettre G, Orkin SH. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science 2013; 342:253-7. PubMed
  • Doulatov S, Vo LT, Chou SS, Kim PG, Arora N, Li H, Hadland BK, Bernstein ID, Collins JJ, Zon LI, Daley GQ. Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via respecification of lineage-restricted precursors. Cell Stem Cell 2013; 13:459-70. PubMed
  • Toms AV, Deshpande A, McNally R, Jeong Y, Rogers JM, Kim CU, Gruner SM, Ficarro SB, Marto JA, Sattler M, Griffin JD, Eck MJ. Structure of a pseudokinase-domain switch that controls oncogenic activation of Jak kinases. Nat Struct Mol Biol 2013; 20:1221-3. PubMed
  • Guo G, Luc S, Marco E, Lin TW, Peng C, Kerenyi MA, Beyaz S, Kim W, Xu J, Das PP, Neff T, Zou K, Yuan GC, Orkin SH. Mapping cellular hierarchy by single-cell analysis of the cell surface repertoire. Cell Stem Cell 2013; 13:492-505. PubMed
  • Reschke M, Clohessy JG, Seitzer N, Goldstein DP, Breitkopf SB, Schmolze DB, Ala U, Asara JM, Beck AH, Pandolfi PP. Characterization and analysis of the composition and dynamics of the mammalian riboproteome. Cell Rep 2013; 4:1276-87. PubMed
  • Kim W, Bird GH, Neff T, Guo G, Kerenyi MA, Walensky LD, Orkin SH. Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nat Chem Biol 2013; 9:643-50. PubMed
  • Miller PG, Al-Shahrour F, Hartwell KA, Chu LP, Järås M, Puram RV, Puissant A, Callahan KP, Ashton J, McConkey ME, Poveromo LP, Cowley GS, Kharas MG, Labelle M, Shterental S, Fujisaki J, Silberstein L, Alexe G, Al-Hajj MA, Shelton CA, Armstrong SA, Root DE, Scadden DT, Hynes RO, Mukherjee S, Stegmaier K, Jordan CT, Ebert BL. In Vivo RNAi screening identifies a leukemia-specific dependence on integrin beta 3 signaling. Cancer Cell 2013; 24:45-58. PubMed
  • Song SJ, Ito K, Ala U, Kats L, Webster K, Sun SM, Jongen-Lavrencic M, Manova-Todorova K, Teruya-Feldstein J, Avigan DE, Delwel R, Pandolfi PP. The oncogenic microRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation. Cell Stem Cell 2013; 13:87-101. PubMed
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