Loss of arpc5 in hematopoietic cells leads to systemic myeloproliferation in vivo

Arp2/3 is a seven-subunit complex that is responsible for generating branched actin networks, which are essential for many biological processes. In mammals, three of the seven subunits exist as two isoforms (Arp3/3B, ARPC1A/1B, ARPC5/5L) resulting in eight Arp2/3 iso-complexes with different properties. Our recent collaborative work demonstrates that patients with ARPC5-deficiency have severe immunological problems and suffer early demise from sepsis (Sindram et al., BioRxiv, 2023). We now show that unchallenged hematopoietic-specific ARPC5-KO mice have two major physiological phenotypes – pale bone marrow and splenomegaly. Further analysis revealed profound systemic myelopoiesis and reduced medullary erythropoiesis. Characterization of the hematopoietic stem and progenitor cells (HSPC) showed a significant increase in hematopoietic stem cell (HSC) numbers, myeloid biased-lineage commitment, and extensive extramedullary hematopoiesis in the mice. We have also detected increased production of inflammatory cytokines in circulation and evidence of HSPC mobilization out of the marrow compartment. In summary, hematopoietic-specific loss of ARPC5 results in characteristics resembling pre-leukemic myeloproliferation and our ongoing work is aimed at understanding the underlying mechanism. Arp2/3 is a seven-subunit complex that is responsible for generating branched actin networks, which are essential for many biological processes. In mammals, three of the seven subunits exist as two isoforms (Arp3/3B, ARPC1A/1B, ARPC5/5L) resulting in eight Arp2/3 iso-complexes with different properties. Our recent collaborative work demonstrates that patients with ARPC5-deficiency have severe immunological problems and suffer early demise from sepsis (Sindram et al., BioRxiv, 2023). We now show that unchallenged hematopoietic-specific ARPC5-KO mice have two major physiological phenotypes – pale bone marrow and splenomegaly. Further analysis revealed profound systemic myelopoiesis and reduced medullary erythropoiesis. Characterization of the hematopoietic stem and progenitor cells (HSPC) showed a significant increase in hematopoietic stem cell (HSC) numbers, myeloid biased-lineage commitment, and extensive extramedullary hematopoiesis in the mice. We have also detected increased production of inflammatory cytokines in circulation and evidence of HSPC mobilization out of the marrow compartment. In summary, hematopoietic-specific loss of ARPC5 results in characteristics resembling pre-leukemic myeloproliferation and our ongoing work is aimed at understanding the underlying mechanism.