Leukemia and hematopoietic stem cells: balancing proliferation and quiescence

Abstract

Chromosomal translocations that disrupt transcriptional regulators are frequently involved in the etiology of leukemia. To gain an understanding of the normal and pathologic roles of these transcriptional regulators, both gain- and loss-of-function mutations have been examined in the context of steady-state hematopoiesis. These studies have identified a remarkable number of genes whose loss-of-function phenotype includes a perturbation of hematopoietic stem cell (HSC) proliferation. As more of these models are generated and analyzed using commonly available tools, the regulatory pathways that control HSC quiescence and proliferation are becoming clearer. An emerging theme is that leukemia-associated transcriptional regulators coordinate the balance of proliferation and quiescence within the HSC pool by modulating the number and frequency of cells transiting the cell cycle. Uncoupling proliferation from differentiation by the aberrant generation of chimeric oncogenes that retain some, but not all of the attributes of the original transcription factor is likely to be an important step during leukemogenesis.

Figure 1

Three basic categories of HSC-specific phenotypes are observed in the knockout animals discussed in this review. Shown are the three categories discussed in this review, their steady-state HSC pool size (circles in the bone icon), and the outcome of primary transplants (indicated on the right for each category). In the first example, wild-type bone marrow cells engraft primary recipients proportional to the number of input cells, indicated by the constant ratio of input cells (left of the mouse) to donor derived cells in the primary transplant recipient (right of the mouse). HNR, homeostatic negative regulators, HB, homeostatic balancer, HPR, homeostatic positive regulator. The closed circles indicate cells from mutant animals and the open circles indicate wild-type competitor bone marrow cells.