Investigating the Role of HIP1/PDGFβR in Leukemogenesis and Imatinib Sensitivity

The Huntingtin interacting protein 1 (HIP1)-platelet-derived growth factor beta receptor (PDGFβR) fusion oncogene (H/P), resulting from a somatic t(5;7) translocation, causes expression of a constitutively active tyrosine kinase and is associated with myelomonocytic leukemia. To gain an understanding of the mechanism of leukemogenesis, we generated a mouse model with a conditional H/P knockin allele. We found that activation of this allele in vivo in hematopoietic cells of adult mice was not sufficient to induce leukemia. However, co-induction with a conditional human t(8;21) AML1-ETO (A/E) knockin allele resulted in a fully penetrant, rapid onset aggressive myeloproliferative disease. The leukemic cells were completely recombined and were uniformly Gr-1 positive. This leukemia was associated with a decreased frequency of hematopoietic stem cells (HSC) in the bone marrow and was sensitive to tyrosine kinase inhibition by imatinib. Imatinib treatment normalized white blood cell counts and restored bone marrow stem cell frequency but unexpectedly increased the ability of the leukemia to be transferred to syngeneic recipients. We show that a leukemia-initiating cell (LIC) persists in vivo during imatinib therapy, shares phenotypic characteristics with HSCs, and does not depend on H/P signaling for survival. Mobilization of the LIC was unable to enhance sensitivity to imatinib. This first example of a conditional knockin mouse model of a leukemogenic tyrosine kinase has facilitated the identification of an A/E cooperating mutation and has shed surprising light on the differential response of different leukemia cells to imatinib targeted therapy. The persistence of an LIC corroborates clinical data and provides a model system for testing of novel therapies. The disparity between different cancer cells in the same tumor is an issue that needs to be resolved and from such models as that described here the resolution of this issue is now more tractable.PhDCellular & Molecular BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91549/1/sphilips_1.pd