Research in the field of cancer biology over the past few years has demonstrated the importance of cancer stem cells, with much of the strongest data emerging from the study of leukemia stem cells (LSCs). LSCs clearly differ from the bulk leukemic cells in a number of ways. These are the cells that are responsible for perpetuation of leukemia over time. In order to eradicate leukemia in a patient it is necessary to eliminate these cells. A fuller understanding of these cells is likely to improve our ability to target them, thereby improving the cure rate for a variety of leukemias. FLT3 is a receptor tyrosine kinase that is mutated frequently to a constitutively activated form in acute myeloid leukemia (AML) and, less frequently, in acute lymphoblastic leukemia (ALL). Many studies have shown that these mutations result in poor prognosis for AML patients. Our long-term objective is to better understand how this frequently mutated oncogene contributes to leukemogenesis in order to develop improved treatments for patients with AML and ALL in which FLT3 plays a role. We have performed experiments that indicate these mutations are usually present in the functional LSC from primary AML samples. We now propose to study how this oncogene contributes to LSC biology. Towards this end, we have developed a mouse model in which we inserted a FLT3/ITD mutation into the murine FLT3 gene. This FLT3/ITD """"""""knock-in"""""""" mouse thus expresses the constitutively activated oncogene under the control of the normal FLT3 promoter and thus expresses it at the appropriate level and in the appropriate cell populations. These mice develop a myeloproliferative disorder in all mice and, less frequently, AML. We will study how other oncogenes known to occur in patients in association with FLT3 mutations cooperate with mutant FLT3 to transform hematopoietic stem-progenitor cells into LSCs. We will determine how the LSC responds to FLT3 tyrosine kinase inhibitors (TKI) and to chemotherapy to increase our understanding of why these leukemias are so difficult to cure. We will also utilize the NOD-scid mouse to study the LSC from patients with FLT3 mutant AML to see if the FLT3 mutation is expressed in the short- and long-term LSC. We will treat mice engrafted with LSCs that have been marked by lentiviral insertion with FLT3 TKI and chemotherapy so that we can study heterogeneity of dependence on FLT3 signaling in LSC as a possible cause of resistance. Lay description: FLT3 is the most frequently mutated gene in acute myeloid leukemia and patients with this mutation have little chance for cure. In this proposal we will study the role of the FLT3 in LSC biology in order to develop better therapies to improve the cure rate for these patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA070970-13
Application #
8212932
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2011-02-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
13
Fiscal Year
2011
Total Cost
$302,992
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Gamper, Christopher J; Takemoto, Clifford M; Chen, Allen R et al. (2016) High-dose Cyclophosphamide is Effective Therapy for Pediatric Severe Aplastic Anemia. J Pediatr Hematol Oncol 38:627-635
Fox, Jennifer M; Moynihan, James R; Mott, Bryan T et al. (2016) Artemisinin-derived dimer ART-838 potently inhibited human acute leukemias, persisted in vivo, and synergized with antileukemic drugs. Oncotarget 7:7268-79
Sharrow, Allison C; Perkins, Brandy; Collector, Michael I et al. (2016) Characterization of aldehyde dehydrogenase 1 high ovarian cancer cells: Towards targeted stem cell therapy. Gynecol Oncol 142:341-8
Kim, MinJung; Tan, Yee Sun; Cheng, Wen-Chih et al. (2015) MIR144 and MIR451 regulate human erythropoiesis via RAB14. Br J Haematol 168:583-97
Candia, Julián; Cherukuri, Srujana; Guo, Yin et al. (2015) Uncovering low-dimensional, miR-based signatures of acute myeloid and lymphoblastic leukemias with a machine-learning-driven network approach. Converg Sci Phys Oncol 1:
Brodsky, Robert A (2014) Paroxysmal nocturnal hemoglobinuria. Blood 124:2804-11
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 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
Tan, Yee Sun; Kim, MinJung; Kingsbury, Tami J et al. (2014) Regulation of RAB5C is important for the growth inhibitory effects of MiR-509 in human precursor-B acute lymphoblastic leukemia. PLoS One 9:e111777
Belet, Stefanie; Fieremans, Nathalie; Yuan, Xuan et al. (2014) Early frameshift mutation in PIGA identified in a large XLID family without neonatal lethality. Hum Mutat 35:350-5

Showing the most recent 10 out of 59 publications