Mechanisms controlling hematopoietic stem cell functions during normal hematopoiesis and hematological malignancies

Abstract

Hematopoiesis, the process by which all mature blood cells are generated from multipotent hematopoietic stem cells (HSCs), is a finely tuned balancing act in which HSCs must constantly decide between different cell fates: to proliferate, to self-renew or differentiate, to stay quiescent in the bone marrow niche or migrate to the periphery, to live or die. These fates are regulated by a complex interplay between cell-extrinsic cues and cell-intrinsic regulatory pathways whose function is to maintain a homeostatic balance between HSC self-renewal and life-long replenishment of lost blood cells. Improper regulation of these competing cellular programs can transform HSCs and progenitor cells into disease-initiating leukemic stem cells (LSCs). Strikingly, many of the mechanisms required for maintenance of normal HSC fate decisions are equally critical for the aberrant functions of LSCs. Because of the inherent complexities of these molecular mechanisms, a systematic approach to understanding the regulatory networks underlying HSC self-renewal is critical for uncovering the similarities and differences between HSCs and LSCs. In this review, we focus on recent developments in elucidating the regulatory networks governing normal HSC self-renewal programs and their implications for leukemic transformation. We describe the current technical and methodological limitations in isolating and characterizing HSCs and LSCs, and the emerging approaches that may afford a better understanding of the regulation of normal and leukemic hematopoiesis. Finally, we discuss how such basic mechanistic information may be of use for the design of novel therapies that will selectively reprogram and/or eliminate LSCs.

Cell cycle regulation in hematopoietic stem cells

“…Specifically, PI3K signaling may accelerate cell proliferation by stabilizing D-type cyclins and inhibiting FoxO-dependent transcription of p21 Cip and p27 Kip1 (Massagué 2004). Attenuation of signaling through the PI3K pathway is essential to preserve HSC quiescence and long-term self-renewal (Warr et al, 2011). Conditional deletion of Pten in the hematopoietic system results in an aggressive and deadly early-onset myeloproliferative neoplasm (MPN), which is accompanied by a threefold increase in the frequency of cycling HSCs (Yilmaz et al, 2006;Zhang et al, 2006).…”

The EBF transcription factor Collier directly promotes Drosophila blood cell progenitor maintenance independently of the niche

“…Blood cells arise from a common multipotent progenitor whose development is tightly controlled to allow on the one hand the maintenance of a pool of progenitors and on the other hand the balanced production of the different hematopoietic lineages (1). This equilibrium is controlled both by intrinsic genetically-encoded determinants and by extrinsic cues such as infection (2).…”

Retroviral Infection of Murine Embryonic Stem Cell Derived Embryoid Body Cells for Analysis of Hematopoietic Differentiation

“…Upon observing phenotypes associated with distinct temporal expression, an investigator may want to now spend the effort to generate inducible lines where the expression of the transgene can be tightly controlled. hematopoietic stem and progenitor cells themselves or sometimes the defect may affect cells in the microenvironment that are needed to support the development of stem and progenitor cells 16,24 . In this system, if the defect is intrinsic to hematopoietic progenitor cells, then reintroduction of the wildtype gene will only rescue hematopoietic development in the GFP+ (retroviral infected) cells.…”