STAT5 in hematopoietic stem cell biology and transplantation

Abstract

Signal transducer and activator of transcription 5 (STAT5) regulates normal lympho-myeloid development through activation downstream of early-acting cytokines, their receptors, and Janus kinases (JAKs). Despite a general understanding of the role of STAT5 in hematopoietic stem cell (HSC) proliferation, survival, and self-renewal, the transcriptional targets and mechanisms of gene regulation that control multi-lineage engraftment following transplantation for the most part remain to be understood. In this review, we focus on the role of STAT5 in HSC transplantation and recent developments toward identifying the relevant downstream target genes and their role as part of a pleiotropic STAT5 mediated signaling response.

Keywords: JAK-STAT; cytokine signaling; engraftment; hematopoiesis; quiescence; self-renewal; stem cell; transplantation.

Figure 1. Conditional knockout strategies for STAT5 deletion in the hematopoietic system. (A) We have previously studied HSC with interferon-induced deletion of STAT5 using the Mx1-Cre system. This approach gives conditional deletion of STAT5 in adult mice. The limitation of the approach is the need to wait for the interferon response to subside before subsequent analysis. (B) Since 2006 various other groups have conditionally knocked out STAT5 floxed alleles of STAT5A and STAT5B that were generated by Lothar Hennighausen (NIDDK). These knockouts include expression of Cre recombinase in early hematopoietic stem cells (and vascular progenitors), as well as T cells, B cells, NK cells, and dendritic cell lineages.

Figure 2. Comparison between STAT5 and Mpl knockout phenotypes. While c-Mpl deficiency causes severe megakaryocyte and platelet production defects, most other lymphoid and myeloid lineages are unaffected. Interestingly, Mpl knockout also selectively impairs early HSC/HPC function as determined by analysis of peripheral blood chimerism following transplantation. STAT5 knockout mice share the common HSC/HPC level defects, do not have intrinsic megakaryocyte/platelet defects, but have severe combined immunodeficiency that is unique to the role of STAT5 downstream of the common gamma chain and JAK3.

Figure 3. Possible hematopoietic stem/progenitor fates in the absence of STAT5. We have observed high levels of HSC/HPC engraftment in mice lacking STAT5. However, due to the strong multilineage selective growth advantage of the wild-type donor cells vs. the STAT5 knockout cells, it has been difficult to assess the impact in HSC vs. HPC compartments of the bone marrow. It is possible that only a subset of niches are vacated in the absence of STAT5 and that competition for these niches is not selectively impaired (homing, engraftment). STAT5 deficient HSC may not leave the niches as part of normal trafficking but rather prevent donor HSC from occupying niches. STAT5 deficient HPC may be vacated from putative HPC niches resulting in greater multilineage engraftment from multipotent progenitors.