title: IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells.
abstract: 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.
authors: Division of Hemato-Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY;
authors: Carolina
authors: C
authors: Schinke
authors: Division of Hemato-Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY;
authors: Orsolya
authors: O
authors: Giricz
authors: Division of Hemato-Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY;
authors: Weijuan
authors: W
authors: Li
authors: Division of Hemato-Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY;
authors: Aditi
authors: A
authors: Shastri
authors: Division of Hemato-Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY;
authors: Shanisha
authors: S
authors: Gordon
authors: Laura
authors: L
authors: Barreyro
authors: Division of Hemato-Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY;
authors: Laura
authors: L
authors: Barreryo
authors: Division of Hemato-Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY;
authors: Tushar
authors: T
authors: Bhagat
authors: Division of Hemato-Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY;
authors: Sanchari
authors: S
authors: Bhattacharyya
authors: Division of Hemato-Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY;
authors: Nandini
authors: N
authors: Ramachandra
authors: Division of Hemato-Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY;
authors: Matthias
authors: M
authors: Bartenstein
authors: Leukemia and Lymphoma Research Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, John Radcliffe Hospital, and National Institute for Health Research Biomedical Research Centre, Oxford, United Kingdom;
authors: Andrea
authors: A
authors: Pellagatti
authors: Leukemia and Lymphoma Research Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, John Radcliffe Hospital, and National Institute for Health Research Biomedical Research Centre, Oxford, United Kingdom;
authors: Jacqueline
authors: J
authors: Boultwood
authors: Department of Medicine, Hematology-Oncology, Cancer Research Center, University of Chicago, Chicago, IL; and.
authors: Amittha
authors: A
authors: Wickrema
authors: Division of Hemato-Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY;
authors: Yiting
authors: Y
authors: Yu
authors: Division of Hemato-Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY;
authors: Britta
authors: B
authors: Will
authors: Department of Immunology, Clinical Immunology, Moffitt Cancer Center, Tampa, FL.
authors: Sheng
authors: S
authors: Wei
authors: Division of Hemato-Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY;
authors: Ulrich
authors: U
authors: Steidl
authors: Division of Hemato-Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY;
authors: Amit
authors: A
authors: Verma
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D016000:Cluster Analysis; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011379:Prognosis; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016209:Interleukin-8; D023063:Receptors, Interleukin-8B