Abstract
Myelofibrosis (MF) is a disease associated with high unmet medical needs because allogeneic stem cell transplantation is not an option for most patients, and JAK inhibitors are generally effective for only 2 to 3 years and do not delay disease progression. MF is characterized by dysplastic megakaryocytic hyperplasia and progression to fulminant disease, which is associated with progressively increasing marrow fibrosis. Despite evidence that the inflammatory milieu in MF 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 the development of fibrosis, coupled with the analysis of bone marrow populations using single-cell RNA sequencing. We found high interleukin 13 (IL-13) levels in the bone marrow of MF mice. IL-13 promoted the growth of mutant megakaryocytes and induced surface expression of transforming growth factor β and collagen biosynthesis. Similarly, analysis of samples from patients with MF revealed elevated levels of IL-13 in the plasma and increased IL-13 receptor expression in marrow megakaryocytes. In vivo, IL-13 overexpression promoted disease progression, whereas reducing IL-13/IL-4 signaling reduced several features of the disease, including fibrosis. Finally, we observed an increase in the number 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2805-2817 |
| Number of pages | 13 |
| Journal | Blood |
| Volume | 140 |
| Issue number | 26 |
| DOIs | |
| State | Published - Dec 29 2022 |
Funding
This work was supported by grants from the National Institutes of Health (NIH), National Cancer Institute (NCI) (grant R35CA253096 ) (J.D.C.) and MPN Research Consortium ( P01CA108671 ) (R.H., R.W., A.R.M., and J.D.C.) and in part by a grant from the NIH, NCI (grant R01CA265009) (J.C.C.). Additional support was provided by the Samuel Waxman Cancer Research Foundation and St. Jude/American Lebanese Syrian Associated Charities (J.D.C.). The authors thank Julie Justice for assistance with immunohistochemistry, the Hartwell Center and the flow core at St. Jude Children's Research Hospital. This work was supported by grants from the National Institutes of Health (NIH), National Cancer Institute (NCI) (grant R35CA253096) (J.D.C.) and MPN Research Consortium (P01CA108671) (R.H. R.W. A.R.M. and J.D.C.) and in part by a grant from the NIH, NCI (grant R01CA265009) (J.C.C.). Additional support was provided by the Samuel Waxman Cancer Research Foundation and St. Jude/American Lebanese Syrian Associated Charities (J.D.C.). The content is the sole the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. J.M.-C. is a fellow of the Leukemia and Lymphoma Society and Mark Foundation for Cancer Research. Contribution: J.M.-C. L.B. A.C. and C.M. designed and performed the experiments and analyzed the data; J.C.C. G.K. J.G. and S.G. analyzed the data; R.W. R.H. Y.Z. M.D. and C.R.R. provided the reagents and/or samples; J.D.C. designed the experiments and analyzed the data; and all authors wrote the manuscript.
ASJC Scopus subject areas
- Biochemistry
- Immunology
- Hematology
- Cell Biology