Myeloid Biology:
Is There a Fork in the Road?

Why is it important if hematopoietic cells differentiate strictly along one lineage pathway, the way we have grown accustomed to seeing illustrated in the familiar stem cell differentiation charts, or retain the ability to make sharp turns and go down a totally different pathway? Is a sharp turn into the lymphoid or myeloid differentiation pathways really what happens to bipotent cells, or are these cells poised to differentiate one way versus another based on important fate-determining decisions that take place prior to any final commitment?

Today at 10:15 a.m. and 4:15 p.m., the Scientific Committee on Myeloid Biology session chaired by Dr. Mary C. Dinauer (Indiana University) will discuss Fate Determinants in Myeloid Development, a topic that will include the role of lineage-restricted transcription factors in the specification of differentiation and undoubtedly shed light on how progenitor cells commit to differentiation.

The panel of scientists assembled to take on this topic will give us answers from their experiences with normal mammalian progenitors (Dr. Thomas Graf from the Albert Einstein College of Medicine), with the Drosophila hematopoietic system (Dr. Utpal Banerjee from the University of California-Los Angeles), and with hematologic malignancies, especially acute myeloid leukemias (Dr. Michael Cleary, Stanford University).

Dr. Graf will begin by describing the effect of enforced transcription factor expression in committed B and T cell precursors from bone marrow and thymus. Viral-mediated expression of the C/EBP transcription factors, known to regulate the expression of myelomonocytic genes, induced a rapid reprogramming of lymphoid precursors into macrophage-like cells. Expression of the C/EBP factors alone was sufficient to downregulate lymphoid markers, whereas the upregulation of myelomonocytic gene expression required the co-expression of endogenous PU.1, another myeloid transcription factor. Therefore, it is possible that stochastic events establish the dominance of C/EBP bipotent lymphoid/myeloid progenitors to commit to the macrophage differentiation pathway, while in the absence of C/EBP expression, the same progenitor takes a lymphoid differentiation pathway.

Dr. Banerjee will describe the Drosophila transcriptional hierarchy that is required for blood cell formation in order to draw parallels, at the molecular level, between the development of the Drosophila cardiogenic mesoderm and the mammalian Aorta-Gonadal-mesonephros mesoderm. Early commitment decisions in the Drosophila hemangioblast will be presented in clonal studies whereby one daughter cell of the hemangioblast can differentiate into blood while the other differentiates into heart/aorta. The discussion will then move to how alterations in transcription factors impact the behavior of myeloid progenitors in acute myeloid leukemia. Dr. Cleary will explain how a key pathological feature of AML is the shift in the balance between differentiation and self-renewal of hematopoietic stem cells. Transcription factors important in the regulatory mechanisms of normal stem cells become the targets of mutations in AML. The Hox proteins are an important group of gene regulators which have been shown to play fundamental roles in stem cell proliferation, differentiation, and self-renewal. The proto-oncoprotein, mixed lineage leukemia (MLL) is itself a Hox gene regulator, suggesting that AML may arise from mutations to the Hox genes or their upstream regulators. MLL is considered to be an epigenetic regulator, and this function is corrupted in AML by mutations in MLL that lead to persistent Hox gene expression and a breakdown in the regulation of differentiation versus self-renewal. The impact of these studies on the development of therapeutic strategies targeting the MLL-Hox axis will be presented.