Proinflammatory signaling is a hallmark of myeloproliferative neoplasms. Several studies have shown that monocytes are a major source of proinflammatory cytokines and that monocyte-derived fibrocytes play a pivotal role in the pathogenesis of myelofibrosis (MF). To further explore the role of monocytes in MF, we generated inducible NrasG12D/+Jak2V617F/+ (NJ) mice. Recipients transplanted with NJ bone marrow (BM) cells developed MF with an early onset of anemia and monocytosis. In vitro, NJ recipients' BM nucleated cells exhibited an increased quantity of CD45+CollagenI+ fibrocytes, which were mainly derived from the Ly6chigh monocytes. RNA sequencing identified a significant elevated expression of CD38 (a NAD+ ... More
Proinflammatory signaling is a hallmark of myeloproliferative neoplasms. Several studies have shown that monocytes are a major source of proinflammatory cytokines and that monocyte-derived fibrocytes play a pivotal role in the pathogenesis of myelofibrosis (MF). To further explore the role of monocytes in MF, we generated inducible NrasG12D/+Jak2V617F/+ (NJ) mice. Recipients transplanted with NJ bone marrow (BM) cells developed MF with an early onset of anemia and monocytosis. In vitro, NJ recipients' BM nucleated cells exhibited an increased quantity of CD45+CollagenI+ fibrocytes, which were mainly derived from the Ly6chigh monocytes. RNA sequencing identified a significant elevated expression of CD38 (a NAD+ hydrolase) in Ly6chigh monocytes from NJ mice, which results in a pronounced lower level of NAD+. In humans, CD14+ monocytes from patients with MF showed a significantly higher expression of CD38 than controls and monocytes from patients with polycythemia vera with grade 1 fibrosis had higher CD38 expression than those without fibrosis. Finally, boosting NAD+ via pharmacological CD38 targeting or NAD+ precursor supplementation inhibited the differentiation of fibrocytes in vitro and targeting CD38 can effectively prevent the onset of fibrosis in vivo. Collectively, our findings shed light on the role of CD38 in monocytes and suggest potential clinical applications such as the use of CD38 as a biomarker of fibrotic progression and the clinical utility of CD38 inhibition in patients with MF.
