Targeting CD38 effectively prevents myelofibrosis in myeloproliferative neoplasms

Abstract

Proinflammatory signaling is a hallmark of myeloproliferative neoplasms (MPNs). Several studies have shown that monocytes are a major source of proinflammatory cytokines and 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 cells developed MF with an early onset of anemia and monocytosis. In vitro, NJ recipients bone marrow nucleated cells exhibited increased quantity of CD45+CollagenI+ fibrocytes, which were mainly derived from the Ly6chigh monocytes. RNA sequencing identified a significant elevated expression of CD38 (a nicotinamide adenine dinucleotide (NAD)+ hydrolase) in Ly6chigh monocytes from NJ mice, which results in pronounced lower level of NAD+. In humans, CD14+ monocytes from MF patients showed significantly higher expression of CD38 than controls and monocytes from polycythemia vera (PV) patients with grade 1 fibrosis had higher CD38 expression than those without fibrosis. Finally, we tested that boosting NAD+ via pharmacological CD38 targeting or NAD+ precursor supplementation inhibited the differentiation of fibrocytes in vitro and observed that 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 use of CD38 as a biomarker of fibrotic progression and potential clinical utility of CD38 inhibition in patients with MF. Key PointsO_LICD38-overexpressing monocytes are increased in MF murine models and MPN patients progressing to fibrotic-phase disease. C_LIO_LIRestoring intracellular NAD+ levels using the CD38 inhibitor 78c prevented the development of fibrotic-phase disease in MPN murine models. C_LI