TY - JOUR
T1 - IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells
AU - Schinke, Carolina
AU - Giricz, Orsolya
AU - Li, Weijuan
AU - Shastri, Aditi
AU - Gordon, Shanisha
AU - Barreyro, Laura
AU - Bhagat, Tushar
AU - Bhattacharyya, Sanchari
AU - Ramachandra, Nandini
AU - Bartenstein, Matthias
AU - Pellagatti, Andrea
AU - Boultwood, Jacqueline
AU - Wickrema, Amittha
AU - Yu, Yiting
AU - Will, Britta
AU - Wei, Sheng
AU - Steidl, Ulrich
AU - Verma, Amit
N1 - Funding Information:
This work was supported by the Leukemia Lymphoma Society, Department of Defense, and National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK1039615 and National Heart, Lung, and Blood Institute grant R01HL116336.
Publisher Copyright:
© 2015 by The American Society of Hematology.
PY - 2015
Y1 - 2015
N2 - Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Novel therapeutic targets against preleukemic stem cells need to be identified for potentially curative strategies. We conducted parallel transcriptional analysis of highly fractionated stem and progenitor populations in MDS, AML, and control samples and found interleukin 8 (IL8) to be consistently overexpressed in patient samples. The receptor for IL8, CXCR2, was also significantly increased in MDS CD34+ cells from a large clinical cohort and was predictive of increased transfusion dependence. High CXCR2 expression was also an adverse prognostic factor in The Cancer Genome Atlas AML cohort, further pointing to the critical role of the IL8-CXCR2 axis in AML/MDS. Functionally, CXCR2 inhibition by knockdown and pharmacologic approaches led to a significant reduction in proliferation in several leukemic cell lines and primary MDS/AML samples via induction of G0/G1 cell cycle arrest. Importantly, inhibition of CXCR2 selectively inhibited immature hematopoietic stem cells from MDS/AML samples without an effect on healthy controls. CXCR2 knockdown also impaired leukemic growth in vivo. Together, these studies demonstrate that the IL8 receptor CXCR2 is an adverse prognostic factor in MDS/AML and is a potential therapeutic target against immature leukemic stem cell-enriched cell fractions in MDS and AML.
AB - Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Novel therapeutic targets against preleukemic stem cells need to be identified for potentially curative strategies. We conducted parallel transcriptional analysis of highly fractionated stem and progenitor populations in MDS, AML, and control samples and found interleukin 8 (IL8) to be consistently overexpressed in patient samples. The receptor for IL8, CXCR2, was also significantly increased in MDS CD34+ cells from a large clinical cohort and was predictive of increased transfusion dependence. High CXCR2 expression was also an adverse prognostic factor in The Cancer Genome Atlas AML cohort, further pointing to the critical role of the IL8-CXCR2 axis in AML/MDS. Functionally, CXCR2 inhibition by knockdown and pharmacologic approaches led to a significant reduction in proliferation in several leukemic cell lines and primary MDS/AML samples via induction of G0/G1 cell cycle arrest. Importantly, inhibition of CXCR2 selectively inhibited immature hematopoietic stem cells from MDS/AML samples without an effect on healthy controls. CXCR2 knockdown also impaired leukemic growth in vivo. Together, these studies demonstrate that the IL8 receptor CXCR2 is an adverse prognostic factor in MDS/AML and is a potential therapeutic target against immature leukemic stem cell-enriched cell fractions in MDS and AML.
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U2 - 10.1182/blood-2015-01-621631
DO - 10.1182/blood-2015-01-621631
M3 - Article
C2 - 25810490
AN - SCOPUS:84929385369
SN - 0006-4971
VL - 125
SP - 3144
EP - 3152
JO - Blood
JF - Blood
IS - 20
ER -
