Our long-term goals are to increase the cure rate and decrease chemotherapy-related toxicity for patients with leukemia. FLT3 is a receptor tyrosine kinase that is one of the most frequently mutated genes in acute myeloid leukemia and is also less frequently mutated in ALL. The mutations result in constitutive activation of the kinase activity of FLT3 that contributes to transformation of normal hematopoietic cells. The group of patients with mutations has particularly poor outcomes with cure rates in the 10-20% range in pediatric and adult populations. While there are several gene alterations (mostly translocations involving transcription factors) known to occur together with FLT3 mutations, most FLT3 mutations occur in patients with normal karyotypes. It is likely that there are other second "hits" in these patients cooperating with FLT3 but the genes are likely affected by point mutations or small deletions or insertions that are not recognized by cytogenetics. One way to discover some of these genes is to determine the spectrum of genes that can cooperate with FLT3/ITD mutations in leukemogenesis. We will follow a strategy of retroviral insertion mutagenesis (RIM) in mice that we have engineered to express a FLT3/ITD mutation. We will also engineer a mouse that expresses a FLT3 kinase domain mutation and take a parallel approach to see if the phenotype of leukemia that results and spectrum of genes that cooperate are overlapping but different from the FLT3/ITD results as the behavior of AML patients with KD mutations is different from those with ITD mutations. We will then screen samples from patients with FLT3 mutant leukemias with normal cytogenetics for the presence of mutations or upregulation of these genes. We will also assess the response of the leukemias that develop in both types of mutant FLT3 mice to FLT3 tyrosine kinase inhibitors (TKI). Finally, we will determine the spectrum of activity of available FLT3 TKI against the many different types of KD mutations that have been reported in patients. Lay description: FLT3 is the most frequently mutated gene in acute myeloid leukemia and patients with this mutation have little chance for cure. We are studying how these mutations combine with alterations in other genes to cause normal blood cells to become leukemic. This will enable us to better attack these leukemias at the molecular level to improve the chance of cure and decrease the toxicities of chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090668-10
Application #
8197222
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Mufson, R Allan
Project Start
2001-04-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
10
Fiscal Year
2012
Total Cost
$284,804
Indirect Cost
$111,143
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Galanis, Allison; Ma, Hayley; Rajkhowa, Trivikram et al. (2014) Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood 123:94-100
Ma, Hayley S; Nguyen, Bao; Duffield, Amy S et al. (2014) FLT3 kinase inhibitor TTT-3002 overcomes both activating and drug resistance mutations in FLT3 in acute myeloid leukemia. Cancer Res 74:5206-17
Rau, Rachel; Magoon, Daniel; Greenblatt, Sarah et al. (2014) NPMc+ cooperates with Flt3/ITD mutations to cause acute leukemia recapitulating human disease. Exp Hematol 42:101-13.e5
Ma, Hayley; Nguyen, Bao; Li, Li et al. (2014) TTT-3002 is a novel FLT3 tyrosine kinase inhibitor with activity against FLT3-associated leukemias in vitro and in vivo. Blood 123:1525-34
Heiser, Diane; Tan, Yee Sun; Kaplan, Ian et al. (2014) Correlated miR-mRNA expression signatures of mouse hematopoietic stem and progenitor cell subsets predict "Stemness" and "Myeloid" interaction networks. PLoS One 9:e94852
Bailey, Emily J; Duffield, Amy S; Greenblatt, Sarah M et al. (2013) Effect of FLT3 ligand on survival and disease phenotype in murine models harboring a FLT3 internal tandem duplication mutation. Comp Med 63:218-26
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Greenblatt, Sarah; Li, Li; Slape, Christopher et al. (2012) Knock-in of a FLT3/ITD mutation cooperates with a NUP98-HOXD13 fusion to generate acute myeloid leukemia in a mouse model. Blood 119:2883-94
Levis, Mark; Ravandi, Farhad; Wang, Eunice S et al. (2011) Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood 117:3294-301

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