Understanding Human Oncogene Function and Cooperativity in Myeloid Malignancy Using iPSCs

Myeloid malignancies are a spectrum of clonal disorders driven by genetic alterations that cooperatively confer aberrant self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs). Induced pluripotent stem cells (iPSCs) can be differentiated into HSPCs and have been widely explored for modeling hematologic disorders and cell therapies. More recently, iPSC models have been applied to study the origins and pathophysiology of myeloid malignancies, motivated by the appreciation for the differences in human oncogene function and the need for genetically defined models that recapitulate leukemia development. In this review, we will provide a broad overview of the rationale, the challenges, practical aspects, history, and recent advances of iPSC models for modeling myeloid neoplasms. We will focus on the insights into the previously unknown aspects of human oncogene function and cooperativity gained through the use of these models. It is now safe to say that iPSC models are a mainstay of leukemia modeling "toolbox" alongside primary human cells from normal and patient sources.