当前位置： SCI文献检索 > CANCER RESEARCH期刊下所有文献 > BCR-ABL-induced deregulation of the IL-33/ST2 pathway in CD34+ progenitors from chronic myeloid leukemia patients.

BCR-ABL-induced deregulation of the IL-33/ST2 pathway in CD34+ progenitors from chronic myeloid leukemia patients.

Abstract：

: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.

journal_name

Cancer Res

journal_title

Cancer research

authors

Levescot A,Flamant S,Basbous S,Jacomet F,Féraud O,Anne Bourgeois E,Bonnet ML,Giraud C,Roy L,Barra A,Chomel JC,Turhan A,Guilhot F,Girard JP,Gombert JM,Herbelin A

doi

10.1158/0008-5472.CAN-13-2797

subject

Has Abstract

pub_date

2014-05-15 00:00:00

pages

2669-76

issue

eissn

0008-5472

issn

1538-7445

pii

0008-5472.CAN-13-2797

journal_volume

pub_type

杂志文章

在线工具

BCR-ABL-induced deregulation of the IL-33/ST2 pathway in CD34+ progenitors from chronic myeloid leukemia patients.