IL-13/IL-4 signaling contributes to fibrotic progression of the myeloproliferative neoplasms

Abstract

Myelofibrosis (MF) is a disease associated with high unmet medical needs since allogeneic stem cell transplantation is not an option for most patients and JAK inhibitors are generally effective for only 2-3 years and do not delay disease progression. MF is characterized by the presence of dysplastic megakaryocytic hyperplasia and progression to fulminant disease, which is associated with progressively increasing marrow fibrosis. Despite evidence of an inflammatory milieu in MF that contributes to disease progression, the specific factors that promote megakaryocyte growth are poorly understood. Here, we analyzed changes in the cytokine profiles of MF mouse models before and after development of fibrosis coupled with analysis of bone marrow populations by scRNA-seq. We found high IL-13 levels in the bone marrow of MF mice. IL-13 promoted the growth of mutant megakaryocytes and induced the surface expression of TGF-b and collagen biosynthesis. Analysis of samples from patients with myelofibrosis similarly revealed elevated levels of IL-13 in plasma and increased IL-13 receptor expression by marrow megakaryocytes. In vivo, IL-13 overexpression promoted disease progression while reducing IL-13/IL-4 signaling reduced several features of the disease including fibrosis. Lastly, we found an increase in the numbers of marrow T cells and mast cells, which are known sources of IL-13. Together, our data demonstrate that IL-13 is involved in disease progression in MF and that inhibition of the IL-13/IL-4 signaling pathway might serve as a novel therapeutic target to treat MF.

SHP2 inhibition displays efficacy as a monotherapy and in combination with JAK2 inhibition in preclinical models of myeloproliferative neoplasms

“…17 IL-33, IL-6, TNFα, TGFβ, IL-13, and CXCL8/IL-8 have been identified as contributing to the pathogenesis of MPNs. [63][64][65][77][78][79][80][81][82][83][84][85][86][87][88][89] The addition of RMC-4550 to ruxolitinib in our studies drove the levels of TNFα, which contributes to clonal expansion in MPN models, 63 below those detected after vehicle and ruxolitinib monotherapy. While BET inhibition antagonizes MPN associated inflammatory signals via suppression of NFκB activity, 73 SHP2 has been implicated in positively regulating signaling by IL-1β, [90][91][92] IL-6, 93,94 CXCL8/IL-8, 95,96 as well as IL-13, 97 which has recently been implicated in driving myelofibrosis in MPN models.…”

Clonal architecture evolution in Myeloproliferative Neoplasms: from a driver mutation to a complex heterogeneous mutational and phenotypic landscape

“…The mechanisms of clonal selection are still poorly understood but several factors may play a role such as cell metabolism, competition for nutrients, clone-to-clone interactions, and cellular microenvironment including soluble factors such as cytokines but also drugs administered to patients. Indeed specific inflammatory cytokines such as IL-1β and IL-13 have recently been shown to be a major factor favoring JAK2 V617F -mutated cells clonal expansion and bone marrow fibrosis in mouse models [ 66 , 67 ]. Mutations in TP53 leading to inactive forms of the protein are identified in 15% of chronic MPNs and are considered key events in the transformation into secondary acute leukemia.…”

Inflammation and bone marrow fibrosis: novel immunotherapeutic targets

“…Mast cells and T cells have been identified as cellular source of IL-13 in the BM. In the MPL W515L mouse model, IL-13 was found to promote megakaryopoiesis, inflammation and collagen biosynthesis in the BM [32 ▪ ]. Deletion of IL-4ra receptor, a common chain of the multimeric IL-4/IL-13 receptors, reduced MF, decreased spleen weight and prolonged survival in mice [32 ▪ ].…”

“…In the MPL W515L mouse model, IL-13 was found to promote megakaryopoiesis, inflammation and collagen biosynthesis in the BM [32 ▪ ]. Deletion of IL-4ra receptor, a common chain of the multimeric IL-4/IL-13 receptors, reduced MF, decreased spleen weight and prolonged survival in mice [32 ▪ ]. Conversely, IL-13 overexpression in JAK2 V617F mice promoted features of MPN [12,33].…”