The role of the atypical chemokine receptor CCRL2 in myelodysplastic syndrome and secondary acute myeloid leukemia-Reference-Cited by-同舟云学术

The role of the atypical chemokine receptor CCRL2 in myelodysplastic syndrome and secondary acute myeloid leukemia

Published:2022-02-18 Issue:7 Volume:8 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Karantanos Theodoros¹^ORCID,Teodorescu Patric¹^ORCID,Perkins Brandy¹,Christodoulou Ilias¹^ORCID,Esteb Christopher¹,Varadhan Ravi²^ORCID,Helmenstine Eric¹,Rajkhowa Trivikram¹^ORCID,Paun Bogdan C.¹,Bonifant Challice¹³^ORCID,Dalton W. Brian¹^ORCID,Gondek Lukasz P.¹^ORCID,Moliterno Alison R.⁴^ORCID,Levis Mark J.¹,Ghiaur Gabriel¹^ORCID,Jones Richard J.¹^ORCID

Affiliation:

1. Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, MD, USA.

2. Division of Biostatistics and Bioinformatics, Johns Hopkins/Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.

3. Department of Pediatrics, Johns Hopkins University Hospital, Baltimore, MD, USA.

4. Division of Adult Hematology, Department of Medicine, Johns Hopkins University, Baltimore MD, USA.

Abstract

The identification of new pathways supporting the myelodysplastic syndrome (MDS) primitive cells growth is required to develop targeted therapies. Within myeloid malignancies, men have worse outcomes than women, suggesting male sex hormone–driven effects in malignant hematopoiesis. Androgen receptor promotes the expression of five granulocyte colony-stimulating factor receptor–regulated genes. Among them, CCRL2 encodes an atypical chemokine receptor regulating cytokine signaling in granulocytes, but its role in myeloid malignancies is unknown. Our study revealed that CCRL2 is up-regulated in primitive cells from patients with MDS and secondary acute myeloid leukemia (sAML). CCRL2 knockdown suppressed MDS92 and MDS-L cell growth and clonogenicity in vitro and in vivo and decreased JAK2/STAT3/STAT5 phosphorylation. CCRL2 coprecipitated with JAK2 and potentiated JAK2-STAT interaction. Erythroleukemia cells expressing JAK2V617F showed less effect of CCRL2 knockdown, whereas fedratinib potentiated the CCRL2 knockdown effect. Conclusively, our results implicate CCRL2 as an MDS/sAML cell growth mediator, partially through JAK2/STAT signaling.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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