Acute myeloid leukemia (AML) is the most common type of adult leukemia and second most common form of childhood leukemia. Some patients have a good chance of cure because historically we know that if they have certain chromosomes that are altered, those patients have done well in response to chemotherapy. The opposite case is also true. More recently we have been able to find mutations in certain genes that give these same good or bad chances for cure to patients with AML. The human gene called FLT3 was cloned by my lab about 20 years ago. It turns out to be the most frequently mutated gene in AML. Not only is it so frequently mutated, but the most common type of FLT3 mutation (called ITD) also gives a very aggressive leukemia with a horrible chance of cure for the AML patients who have the mutation. For example, in pediatric AML, patients without the mutation have a 50-60% chance of cure but those with a FLT3/ITD mutation have only a 15-20% chance of cure. Thus, to improve the chance for curing these patients we need to find ways to reverse the very lethal aggressive nature imparted to the leukemia by way that FLT3 signals in the cell. One of the ways we have attacked this problem was to find the first drugs that were able to block how c signals. This is called a """"""""tyrosine kinase inhibitor"""""""" or TKI. We showed that this would preferentially kill leukemia cells with the FLT3/ITD mutation while leaving normal cells alone. Later generations of these FLT3 TKI are in advanced clinical trials to try to improve the cure rate for FLT3/ITD AML patients. Another type of FLT3 mutation, called a """"""""kinase domain"""""""" or KD mutation, does not give patients with AML a worse chance for cure. This gives us the opportunity to try to learn how the 2 different kinds of mutations in the same gene can lead to such different outcomes. If we can understand how the ITD vs. KD mutations of FLT3 signal differently, it should point out the pathway that results in really bad, difficult to cure leukemias. These same pathways are likely to be used by other leukemias and possibly other types of cancers and so identifying them will be the first step followed by targeting them to improve the cure rate for these diseases. Because patient leukemias have combinations of so many different types of mutations, it is not possible to sort out the signaling differences between them that are due to FLT3/ITD vs. FLT3/KD mutations. To overcome this problem we have generated mice in which we genetically engineered them to be born with either of the two types of mutations. These mice are genetically identical other than the type of FLT3 mutations we have engineered so when we combine them with the same """"""""second hits"""""""" required to generate leukemia any differences between the leukemias are a result of differences in how the FLT3 mutations function. This will enable us to determine what gives the ITD mutations its """"""""bad"""""""" characteristics. We can develop targeted therapies for this """"""""bad"""""""" pathway that is likely used by other difficult to cure leukemias and perhaps other cancers.

Public Health Relevance

Mutations in the FLT3 gene are the most common mutation in acute myeloid leukemia (AML) and patients with this mutation have very little chance for cure. We have developed genetically engineered mouse models that accurately recapitulate what happens in people who develop AML with FLT3 mutations. We are using these mice to better understand leukemia and develop improved therapies to improve the cure rate for these patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Molecular and Cellular Hematology (MCH)
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Mufson, R Allan
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Johns Hopkins University
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Lee, Lauren Y; Hernandez, Daniela; Rajkhowa, Trivikram et al. (2016) Pre-clinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood :
Wu, M; Hamaker, M; Li, L et al. (2016) DOCK2 interacts with FLT3 and modulates the survival of FLT3-expressing leukemia cells. Leukemia :
Ma, Hayley S; Greenblatt, Sarah M; Shirley, Courtney M et al. (2016) All-trans retinoic acid synergizes with FLT3 inhibition to eliminate FLT3/ITD+ leukemia stem cells in vitro and in vivo. Blood 127:2867-78
Poitras, Jennifer L; Heiser, Diane; Li, Li et al. (2016) Dnmt3a deletion cooperates with the Flt3/ITD mutation to drive leukemogenesis in a murine model. Oncotarget :
Lim, Yiting; Gondek, Lukasz; Li, Li et al. (2015) Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia. Sci Transl Med 7:291ra96
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
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
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
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

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