Unfolded protein response signaling promotes myeloid cell production and cooperates with oncogenic mutation

Unfolded protein response (UPR) is an evolutionally conserved adaptive mechanism that promotes protein homeostasis under endoplasmic reticulum (ER) stress. UPR signaling has numerous functions in metabolism, cancer, immunology, and neurodegenerative diseases. Recent studies also showed that UPR signaling has important roles in hematopoietic stem and progenitor cell biology. However, whether UPR signaling regulates hematopoietic lineage fate decision remains elusive. Here, we found that FcγR^- MPP3 generates erythroid lineage and Jak2 ^V617F mutation leads to overproduction of erythroid cells by expanding FcγR^- MPP3. We showed that UPR signaling increases myeloid cell production through promoting FcγR^- MPP3 transition to granulocyte/macrophage progenitor (GMP) producing FcγR⁺ MPP3 at the expense of erythroid lineage via the XBP1 pathway. Under a disease condition, UPR signaling cooperates with Jak2 ^V617F mutation and exacerbates disease phenotype as increasing red blood cells in a mouse model of polycythemia vera (PV) through the ATF4 pathway. Activation of UPR signaling also increased myeloid output in healthy donor bone marrow MPP cells while skewing the output towards erythroid lineage in PV patient bone marrow MPP cells. Together, our results identify a novel function of UPR signaling in hematopoietic lineage specification and provide critical insights into targeting UPR signaling in hematological malignancies.