Leukemogenic Cascade Induced by a Constitutively Active Neurotrophin Receptor, ΔTrkA.

Various neurotrophins (NT) are expressed in the hematopoietic microenvironment to deliver their signals through TRK receptor tyrosine kinases. Although previous reports suggested a transforming potential of activated TRK signaling in hematopoiesis, the target cells and underlying mechanisms are largely unknown. In this study, we investigated in vivo leukemogenesis of ΔTrkA, a mutant of TRKA isolated from a patient with acute myeloid leukemia (AML). Retroviral expression of ΔTrkA in myeloid 32D cells induced AML at ~4 weeks after transplantation into syngeneic C3H/Hej mice (n=11). C57BL/6J mice (n=15) transplanted with ΔTrkA-transduced primary bone marrow cells developed myeloid and/or lymphoid leukemia with infiltration in multiple organs including bone marrow, spleen, liver, lung, and central nervous system. While activation of a tyrosine kinase generally is not sufficient to cause AML, surprisingly, 7 out of 15 C57BL/6J mice developed a polyclonal AML with a latency of <12 days. This strongly suggests that ΔTrkA is sufficient to block differentiation and promote proliferation of short-term repopulating myeloid progenitor cells. This simultaneous interference with two complementary leukemogenic pathways has not been reported for other oncogenic tyrosine kinases. However, as half of the mice survived this disorder, ΔTrkA does not seem to confer self-renewal properties to transformed blasts. Supporting this hypothesis, transplantation into lethally irradiated secondary recipients did not re-induce polyclonal AML, but rather gave rise to clonal acute lymphoblastic leukemia (ALL) after a latency of >78 days. This suggests that ΔTrkA can also transform long-term repopulating cells with a lymphoid potential. Retroviral insertion site analyses and spectral karyotyping revealed that induction of ALL by ΔTrkA required additional genetic lesions: Leukemic cells showed retroviral insertions in proto-oncogenes Bcl11a and Bcl11b, among others. Characterization of signal transduction demonstrated that PI3K and mTOR-raptor were crucial components of the transforming pathway induced by ΔTrkA. Phospholipase D was an important contributing factor, whereas STAT and MAP kinase pathways were not involved. In summary, our findings reveal potent transforming properties of altered NT receptor signaling in leukemia induction, which are in many respects distinct from other oncogenic tyrosine kinases. We would suggest to further evaluate the role of NT receptor signaling in leukemia pathogenesis, prognosis and treatment.