|Department Affiliations||Oncology, Pediatrics|
|SOM Address||Room 251 Cancer Research Building I|
Obdulio Piloto 2001 – 2006
Melissa Griesemer Wright 2002 – 2008
Kate Greenberg 2003 – 2010
My laboratory concentrates on the role of FLT3 in leukemogenesis. We cloned the human FLT3 gene >20 years ago and showed that it was important in normal hematopoietic stem/progenitor cell function but was also highly expressed by leukemic cells. Somatic mutations of the gene were discovered in leukemic cells that result in constitutive activation of the tyrosine kinase activity of FLT3. While these mutations alone do not transform hematopoietic cells to leukemia, they do result in myeloproliferative disease and can cooperate with additional “hits” to give leukemia. FLT3 mutations are the most frequent genetic alteration in AML with about 1/3 of patients involved. FLT3 signaling requires its tyrosine kinase domain so we carried out a strategy of finding small molecule inhibitors of ATP binding to the active pocket to block kinase activity. These FLT3 inhibitors were able to induce cell death in modeled cells, human leukemia cell lines and primary AML samples expressing constitutively activated FLT3. We developed a high-throughput assay enabling the discovery of potent and selective FLT3 inhibitors. We showed that these inhibitors would work both in vitro and in vivo and have taken these compounds to the clinic for patients with FLT3 mutant AML.
We continue to study the role of normal and mutant FLT3 in normal and leukemic cells, the critical parts of its signal transduction pathway, and how it cooperates with other genetic alterations in the process of leukemic transformation. We genetically engineered mice to express both types of FLT3 mutations and have bred them with mice expressing other mutations found in AML to generate genetically pure models of spontaneous AML. We are studying the contributions made by each of these mutations to leukemigenesis and how we can target the pathways that are activated to develop pure molecularly targeted therapy for FLT3 mutant AML.
- Li L, Zhang L, Fan J, Greenberg K, Desiderio S, Rassool F, Small D. Defective non-homologous end joining blocks B-cell development in FLT3/ITD mice. Blood. 2011 Mar 17;117(11):3131-9. PMC3062315.
- Sato T, Yang X, Knapper S, White P, Smith D, Galkin S, Small D, Burnett A, Levis M. FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood. 2011 Mar 24;117(12):3286-93. PMC3069670.
- Zheng R, Bailey E, Nguyen B, Yang X, Piloto O, Levis M, Small D. Further activation of FLT3 mutants by FLT3 ligand. Oncogene. 2011;30:4004-14. PMC3155740.
- Li L, Bailey E, Greenblatt S, Huso D, Small D. Loss of the wild-type allele contributes to myeloid expansion and disease aggressiveness in FLT3/ITD knock-in mice. Blood. 2011;118:4935-45. PMC3208299.
- Greenblatt S, Li L, Slape C, Novak R, Duffield A, Huso D, Desiderio S, Borowitz M, Aplan P, Small D. Knock-in of a FLT3 internal tandem duplication mutation cooperates with a NUP98-HOXD13 fusion to generate acute myeloid leukemia in a mouse model. Blood. 2012 Mar 22;119(12):2883-94.
- Kim K, Mossman D, Small D, Scott R. Gene expression profiling of human myeloid leukemic MV4-11 cells treated with 5-aza-2’-deoxycytidine. J. Cancer Therapy. 2012 Jun 20;3(3):177-82.
- Chu S, Heiser D, Li L, Kaplan I, Collector M, Sharkis S, Civin C, Small D. FLT3-ITD knock-in impairs hematopoietic stem cell quiescence/homeostasis, leading to a myeloproliferative neoplasm. Cell Stem Cell. 2012 Sep 7;11(3):346-58. PMC3725984.
- Williams A, Li L, Nguyen B, Brown P, Levis M, Small D. Fluvastatin inhibits FLT3 glycosylation in human and murine cells and prolongs survival of mice with FLT3/ITD leukemia. Blood. 2012 Oct 11;120(15):3069-79. PMC3471516.
- Williams A, Nguyen B, Brown P, Levis M, Leahy D, Small D. Mutations of FLT3 confer resistance to multiple tyrosine kinase inhibitors. Leukemia. 2013 Jan;27(1):48-55. PMC3822911.
- Kim K, Carroll A, Mashkani B, Cairns M, Small D, Scott, R. MicroRNA-16 is down-regulated in mutated FLT3 expressing murine myeloid FDC-P1 cells and interacts with Pim-1. PLOS One. 2012 Sep 6;7(9):e44546. PMC3435263.
- Greenblatt S, Small D. FLT3 lineage specification and plasticity. Oncotarget. 2012 May;3(5):576-80. PMC3388187.
- Sison EA, Rau RE, McIntyre E, Li L, Small D, Brown P. MLL-rearranged acute lymphoblastic leukaemia stem cell interactions with bone marrow stroma promote survival and therapeutic resistance that can be overcome with CXCR4 antagonism. Br J Haematol. 2013 Mar;160(6):785-97. PMC4005340.
- Bailey E, Duffield A, Greenblatt S, Aplan P, Small D. Effect of FLT3 ligand on survival and disease phenotype in murine models harboring a FLT3 internal tandem duplication (ITD) mutation. Comp Med 2013 Jun; 63(3):218-26. PMC3690427.
- Bailey E, Li L, Huso D, Small D. FLT3/D835Y mutation knock-in mice display less aggressive disease compared with FLT3/internal tandem duplication (ITD) mice. Proc Natl Acad Sci USA. 2013 Dec 24; 110(52):21113-18. PMC3876267.
- Galanis A, Ma H, Rajkhowa T, Ramachandran A, Small D, Cortes J, Levis M. Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood 2014 Jan 2(123)1:94-100. PMC3879910.
- Rau R, Magoon D, Greenblatt S, Li L, Annesley C, Duffield A, Huso D, McIntyre E, Clohessy J, Reschke M, Pandolfi PP, Small D, Brown P. Mutated NPMc+ cooperates with Flt3/ITD mutations to cause acute leukemia recapitulating human disease. Experimental Hematology. 2014 Feb;42(2):101-13. PMC 3932758.
- Ma H, Nguyen B, Li L, Greenblatt S, Williams A, Zhao M, Rudek M, Duffield A, Levis M, Small D. TTT-3002 is a novel FLT3 tyrosine kinase inhibitor with activity against FLT3-associated leukemias in vitro and in vivo. Blood 2014 Mar 6;123(10):1525-34. PMC3945863.
- 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 Mar 6;14(3):329-41. PMC4380188.
- Heiser D, Tan YS, Kaplan I, Godsey B, Morisot S, Cheng WC, Small D, Civin CI. Correlated miR-mRNA expression signatures of mouse hematopoietic stem and progenitor cell subsets predict “stemness” and “myeloid” interaction networks. PLOS One, 2014 Apr 18 9(4);e94852. PMC 3991639.
- Lim Y, Gondek L, Li L, Wang Q, Ma H, Chang E, Huso DL, Foerster S, Marchionni L, McGovern K, Watkins DN, Peacock CD, Levis M, Smith BD, Merchant AA, Small D, Matsui W. Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia. Sci Transl Med. 2015 Jun 10;7(291):291ra96. PMID 26062848.