Oncogene cooperation in the pathogenesis of acute myeloid leukemia

The development of acute myeloid leukemia (AML) and the blast phase of chronic myelogenous leukemia (CML-BC) are both characterized by the uncontrolled growth of myeloid cells that have a block in differentiation. Both of their development require multi-step processes that involve the accumulation of several genetic abnormalities. However, the molecular mechanisms by which these genetic alterations act in leukemogenesis are poorly understood.; CML is a good model for multi-step leukemogenesis because its development is characterized by an initial chronic phase and an acute blast phase. BCR/ABL, a constitutively active tyrosine kinase, is a fusion protein generated by the t(9;22)(q34;q11) translocation found in the vast majority of CML patients. BCR/ABL is sufficient to induce the chronic phase of CML, but progression to blast phase requires additional mutations. The AML1/MDS1/EVI1 (AME) transcription factor fusion protein, is a product of the human t(3;21)(q26;q22) translocation found in AML as well as in some cases of CML-BC. BCR/ABL efficiently induces a myeloproliferative disorder (MPD) in mice that resembles only the chronic phase of CML, while the role of AME in leukemogenesis is unclear. Using a murine bone marrow transduction and transplantation approach, I investigated the role of AME alone in AML pathogenesis and whether it can cooperate with BCR/ABL to induce CML-BC.; I found that AME alone does not block myeloid differentiation but induces an AML in mice with a greatly extended latency, suggesting a requirement for secondary mutations. However, co-expression of AME with BCR/ABL/GFP induces a rapid AML in mice suggesting that cooperation between a transcription factor mutation and an activated tyrosine kinase may be a common theme in leukemogenesis. Furthermore, I found that both the AML1 and EVI1 oncogenic components of AME contribute to the pathogenesis of myeloid leukemia, which suggests that induction of AML or development of CML-BC may involve the cooperation of no less than three genetic abnormalities. This AML mouse model can further elucidate the role of AML1, EVI1 and BCR/ABL oncogenes in blocking myeloid differentiation and development of a full-blown leukemia.