American Association for Cancer Research
00085472can132797-sup-fig1.pdf (195.09 kB)

Supplementary Figure 1 from BCR-ABL–Induced Deregulation of the IL-33/ST2 Pathway in CD34(+) Progenitors from Chronic Myeloid Leukemia Patients

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journal contribution
posted on 2023-03-30, 22:00 authored by Anaïs Levescot, Stéphane Flamant, Sara Basbous, Florence Jacomet, Olivier Féraud, Elvire Anne Bourgeois, Marie-Laure Bonnet, Christine Giraud, Lydia Roy, Anne Barra, Jean-Claude Chomel, Ali Turhan, François Guilhot, Jean-Philippe Girard, Jean-Marc Gombert, André Herbelin

PDF file - 200KB, The kinase activity of BCR-ABL induces upregulation of ST2 in UT7 cells.



Although it is generally acknowledged that cytokines regulate normal hematopoiesis in an autocrine/paracrine fashion, their possible role in chronic myelogenous leukemia (CML) and resistance to imatinib mesylate treatment remain poorly investigated. Here, we report that CD34(+) progenitors from patients with CML at diagnosis are selectively targeted by the cytokine/alarmin interleukin (IL)-33. Indeed, CML CD34(+) progenitors upregulate their cell surface expression of the IL-33–specific receptor chain ST2, proliferate and produce cytokines in response to IL-33, conversely to CD34(+) cells from healthy individuals. Moreover, ST2 overexpression is normalized following imatinib mesylate therapy, whereas IL-33 counteracts in vitro imatinib mesylate-induced growth arrest in CML CD34(+) progenitors via reactivation of the STAT5 pathway, thus supporting the notion that IL-33 may impede the antiproliferative effects of imatinib mesylate on CD34(+) progenitors in CML. Clinically, the levels of circulating soluble ST2, commonly considered a functional signature of IL-33 signaling in vivo, correlate with disease burden. Indeed, these elevated peripheral concentrations associated with a high Sokal score predictive of therapeutic outcome are normalized in patients in molecular remission. Finally, we evidenced a facilitating effect of IL-33 on in vivo maintenance of CD34(+) progenitors from patients with CML by using xenotransplant experiments in immunodeficient NOG mice, and we showed that engraftment of mouse BCR-ABL–transfected bone marrow progenitors was less efficient in IL-33–deficient mice compared with wild-type recipients. Taken together, our results provide evidence that IL-33/ST2 signaling may represent a novel cytokine-mediated mechanism contributing to CML progenitor growth and support a role for this pathway in CML maintenance and imatinib mesylate resistance. Cancer Res; 74(10); 2669–76. ©2014 AACR.