Mutations Required for Lymphoid Leukemogenesis Are Not Required for c-Myc to Rapidly Induce Acute Myeloid Leukemia.

Dysregulation of c-Myc is one of the critical oncogenic events required for tumorigenesis in many tissue types. Although c-Myc has been shown to block differentiation of leukemic and normal myeloid cells and is activated by oncogenes commonly found in leukemia, its exact role in myeloid leukmogenesis remains elusive. When c-Myc is over-expressed in the lymphoid compartment, Eμ-Myc transgenic mice develop B-cell lymphomas only after a prolonged latency and require additional mutations to inhibit apoptosis, most commonly by disrupting the Arf-Mdm2-p53 pathway. Although this model has been well used to dissect pathways of Myc-induced lymphomagenesis, there is currently no efficient model with which to study the role of c-Myc in AML. In this study, we utilized a retroviral gene transfer system (MSCV-Myc) to introduce c-Myc into unfractionated murine bone marrow that was subsequently transplanted into syngeneic mice. Surprisingly, 100% of transplanted mice (N=110) from three different strains, developed acute myeloblastic leukemia (AML) characterized by rapid onset, hemiparesis, splenomegaly and infiltration of the marrow and spleen with myeloblasts. c-Myc protein level was comparable to the Eμ-Myc tumors. Disease latency was short (median survival=38 days). MSCV-Myc-induced tumors were oligoclonal, did not display significant cytogenetic abnormalities by SKY analysis, and were exclusively of myeloid origin. These tumors contained germline configuration of the Ink4A locus and wild type coding region of the p53, Arf and Ink4a. Also, the p53 target gene p21 in Myc expressing cells responded normally to gamma irradiation. These data demonstrate that c-Myc induced AML development without disrupting the Arf-p53 pathway and suggest that cooperating mutations were not required for the development of AML. In contrast, using the same retroviral system, lymphoid leukemia developed only if c-Myc and Bcl-2 were co-expressed or if Ink4a was mutated. Tumors from Bcl-2/c-Myc transplanted mice were comprised of a mixture of myeloid and lymphoid leukemic cells. Similarly, mice transplanted with c-Myc transduced Ink4a−/− bone marrow developed leukemia that displayed a mixed phenotype of myeloid and lympoid lineages. Lastly, factor independent methylcellulose colonies induced by Myc were exclusively of myeloid lineage suggesting as intrinsic difference between myeloid and lymphoid cells in response to Myc. Our data imply that dysregulation of c-Myc is sufficient to induce AML and provide direct evidence that Myc is an important downstream target in myeloid leukemogenesis.