A model to explain JAK2^V617F-positive and -negative leukemic transformation in the myeloproliferative disorders. Acquisition of JAK2^V617F by a receptive hematopoietic stem cell (HSC) results in a myeloproliferative disorder (MPD). Acquisition of additional mutations due to genetic instability in the expanding clonal cell population favors spontaneous acute leukemia (AL). Exposure to chemotherapeutic agents that damage DNA but prevent its repair (such as HU) favors the emergence of a clonal constituent that is TP53-independent, can bypass normal replication checkpoints, and continues to acquire genetic damage until it transforms (t-AL). Alternatively, inhibition of more robust members of the dominant clone by chemotherapy may allow a less robust and more unstable clone to dominate. Finally, selective suppression of the JAK^V617F-positive clone by targeted therapy or chemotherapy could lead to selection of a member of the “receptive” ancestral clone or transform it, leading to JAK2^V617F-negative AL or t-AL. (Arrow width indicates event probability; arrow length, the time to transformation.)