BCR-ABL-induced deregulation of the IL-33/ST2 pathway in CD34(+) progenitors from chronic myeloid leukemia patients
Menée à partir d'échantillons sanguins prélevés sur 38 patients atteints d'une leucémie myéloïde chronique et 15 témoins, puis in vitro et in vivo, cette étude met notamment en évidence des mécanismes par lesquels la signalisation IL-33/ST2 favorise la résistance à l'imatinib
Although it is generally acknowledged that cytokines regulate normal hematopoiesis in an autocrine/paracrine fashion, their possible role in chronic myeloid leukemia (CML) and resistance to imatinib mesylate (IM) treatment remain poorly investigated. Here, we report that CD34(+) progenitors from CML patients at diagnosis are selectively targeted by the cytokine/alarmin 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 IM therapy, while IL-33 counteracts in vitro IM-induced growth arrest in CML CD34(+) progenitors via re-activation of the STAT5 pathway, thus supporting the notion that IL-33 may impede the anti-proliferative effects of IM 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 CML patients 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 to 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 IM resistance.