Targeting CD38 effectively prevents myelofibrosis in myeloproliferative neoplasms

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 Nras ^G12D/+ Jak2 ^V617F/+ (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 Ly6c ^high monocytes. RNA sequencing identified a significant elevated expression of CD38 (a nicotinamide adenine dinucleotide (NAD) ⁺ hydrolase) in Ly6c ^high 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.