Remarkable leukemogenic potency and quality of a constitutively active neurotrophin receptor, deltaTrkA.

Neurotrophins and their receptors play a key role in neurogenesis and survival. However, we and others have recently obtained evidence for a potential involvement of this receptor system in leukemia. To investigate mechanisms underlying the leukemogenic potential of activated neurotrophin receptor signaling, we analyzed in vivo leukemogenesis mediated by deltaTrkA, a mutant of TRKA (tropomyosin-related kinase A) isolated from a patient with acute myeloid leukemia (AML). Retroviral expression of deltaTrkA in myeloid 32D cells induced AML in syngeneic C3H/Hej mice (n=11/11, latency approximately 4 weeks). C57Bl/6J mice transplanted with deltaTrkA-transduced primary lineage negative (Lin-) bone marrow cells died of a transient polyclonal AML (n=7/15, latency of <12 days). Serial transplantation of AML cells did not re-induce this disease but rather acute lymphoblastic leukemia (ALL, latency >78 days). All primary recipients surviving the early AML developed clonal ALL or myeloid leukemia (latency >72 days) that required additional genetic lesions. PI3K and mTOR-raptor were identified as the crucial mediators of leukemic transformation, whereas STAT and MAP kinase signaling pathways were not activated. Thus, our findings reveal potent and unique transforming properties of altered neurotrophin receptor signaling in leukemogenesis, and encourage further analyses of neurotrophin receptors and downstream signaling events in hematological malignancies.