Interferon and PV stem cells.

In this issue of Blood, King et al demonstrate a novel mechanism of protection of hematopoietic stem cells by a gene that is negatively regulated by interferon signaling.3 This follows previous papers demonstrating that IFNstimulates normal hematopoietic stem cells from dormancy,4-6 which may eventually lead to depletion of the hematopoietic stem cell pool. Whether this differential effect is more pronounced on normal stem cells or on stem cells dysregulated by somatic mutations (such as those in polycythemia vera), where a yet-to-be-defined single or several somatic mutations generate a clone7,8 which is followed by a clonal evolution marked by JAK2V617F mutation (see figure panel A), remains to be shown. King and coworkers now demonstrate some of the molecular mechanisms of interferon action on the stem cells and report that stem cell expression of Irgm1 gene is essential in preserving the dormancy of stem cells and thus, their number and function. Irgm1 (Lrg-47) is a member of GTPases (IRG) family of genes that are induced by interferon signaling. These genes are known to play a role in innate immunity such as macrophage autophagy–mediated destruction of widerange infectious agents and Irgm1 also regulates the survival of mature effector CD4 T lymphocytes by protecting them from IFN–induced autophagic cell death. King et al followed up on an observation that Irgm1 knockout mouse is not only prone to succumb to nonvirulent infection but is also anemic9 and together with Sher’s NIH laboratory demonstrated that Irgm1 also signals in, and inhibits proliferation of, hematopoietic stem cells and this facilitates their self-renewal.10 In the current article, King et al now demonstrate, using careful studies of hematopoietic stem cell proliferation, self-renewal and regulation of autophagy using the various combination of knockout genotypes of Irgm1, Infngr1 (IFNreceptor 1; Irgm1 / Ifngr1 / ), and STAT1 Irgm1 / Stat1 / ) that the effect of Irgm1 requires intact IFNand that Irgm1 is a potent inhibitor of IFNof stem cell proliferation that may ultimately lead to their depletion via altered self-renewal. Their paper also examined another member of IRG family, Irgm3. It is intriguing that Irgm3 was found to have opposite to or competing functions to Irgm1 in stem cell and they may negatively regulate each other. In summary, this work may provide the missing link to the wellknown effect of hematopoiesis suppression in Effect of IFN on PV stem cells. (A) Simplified scheme of different stem cell compartments in polycythemia vera. Dormant normal stem cells do not contribute to productive hematopoiesis and coexist alongside clonal stem cells with and without JAK2V617F somatic mutation(s). (B) It remains to be determined whether interferon preferentially stimulates proliferation of dormant normal hematopoietic cells, clonal JAK2V617F , or JAK2V617F subclone stem cells. Professional illustration by Alice Y. Chen.