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Understanding drug resistance in pediatric and adult Acute Myeloid Leukemia

Kyle Richard Spinler

Appointment Period: 2015-2016, Grant Year: [29]


Acute Myeloid Leukemia (AML) is a disease associated with multiple cytogenetic abnormalities, the most common of which are those carrying the MLL-fusions. MLL, standing for Myeloid/Lymphoid Or Mixed-Lineage Leukemia, is also known as Lysine (K)-Specific Methyltransferase 2A. MLL functions as a transcriptional coactivator that plays an essential regulatory role during early development and hematopoiesis. In the clinic, drug resistance and relapse often complicate the management of MLLleukemia in both adults and children. There is thus a great need for better understanding of the mechanisms that drive drug resistance and disease relapse.

Based on the fact that expression of the RNA binding protein Musashi2 (Msi2) correlates with poor prognosis, and its high expression has been linked to high incidence of AML relapse, we hypothesize that Msi2 marks and contributes functionally to the drug-resistant population in MLL-leukemia. Further, we hypothesize that the environment surrounding the drug-resistant cells contributes at least in part to the protection and maintenance of the drug-resistant population. To test this we propose to: 1) use Msi2-GFP reporter mice that have been developed in the lab to define whether Msi2+ AML cells are differentially resistant to chemotherapy and if inhibition of Msi2 can sensitize the cancer to chemotherapy; and 2) use dynamic in vivo imaging to identify stromal cells with which the drugresistant cancer cells interact and test whether these cells can promote the survival of chemo-resistant cancer cells. These studies will thus combine molecular analysis of intrinsic elements with innovative real-time imaging of the microenvironment to provide insight into novel determinants of chemoresistance in MLL-leukemia. We anticipate that this work will contribute to the design of combinatorial therapies that target both cell-intrinsic and cell-extrinsic interactions in MLL-leukemia.

PUBLICATIONS (resulting from this training)

Trainee recently appointed to grant: publications are still in progress.