Hematopoietic stem cells in the bone marrow sustain the production of all blood cell lineages through differentiation into progenitors with progressively more restricted lineage potential. Hematopoietic stem cells are remarkably quiescent, are multipotent and have the capacity of self renew. They are the cells that engraft after bone marrow transplantation. Over time they can be become a repository for mutations that give rise to leukemias. Despite decades of research, a coherent understanding of the mechanisms involved in the regulation of their quiescence, self-renewal and differentiation is still lacking however.
Among inbred mouse strains there is extensive genetically determined variation in the function and kinetics of hematopoietic stem and progenitor cells. These traits vary continuously across genetically different individuals as they are determined by the contribution of multiple loci, called quantitative trait loci. We found, through quantitative trait mapping, that allelic variation in the Prdm16 gene plays a role in genetic variation in the hematopoietic system of inbred mouse strains. Using knockout approaches, we discovered that deletion of Prdm16 potently affected HSC maintenance.
We then discovered that one downstream effect of Prdm16 is regulation of mitochondrial fusion and that Prdm16 induces Mitofusin 2 (Mfn2). Deletion of Mfn2 leads to mitochondrial fragmentation and impaired maintenance of subset of HSCs with extensive lymphoid potential. The underlying mechanism is based on regulation of intracellular calcium and NFAT. Further studies focus on the predominantly ATP-independent roles of mitochondria in HSC function, focusing on mitochondrial dynamics, mitochondria-ER interactions, autophagy and mitophagy, and calcium regulation.
Prdm16 is also involved rare translocations that underlie acute myeloid leukemia. The lab is therefore also investigating the role of Prdm16 in leukemogenesis and leukemia progression.
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Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P, Lemischka IR, Zhou BY, Snoeck HW. (2011). Prdm16 is a physiological regulator of hematopoietic stem cells. Blood, 117:267-272.
Luchsinger LL, Justino de Almeida M, Corrigan DJ, Mumau M, Snoeck HW. Mitofusin 2 maintains hematopoietic stem cells with extensive lymphoid potential. Nature, 529(7587):528-531.
Justino M, Luchsinger LL, Williams L, Snoeck HW (2017). Elevated mitochondrial mass in hematopoietic stem cells. Cell Stem Cell 21:725-729.
Snoeck HW (2017). Mitochondrial regulation of hematopoietic stem cells. Curr Opin Cell Biol, 49:91-99.
Corrigan DJ, Luchsinger LL, Williams LJ, de Almeida MJ, Strikoudis A, Snoeck HW (2018). PRDM16 isoforms differentially regulate normal and leukemic hematopoiesis and inflammatory gene signature. J. Clin Invest., in press.