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

Theodoros Karantanos; Patric Teodorescu; Brandy Perkins; Ilias Christodoulou; Christopher Esteb; Ravi Varadhan; Eric Helmenstine; Trivikram Rajkhowa; Bogdan C. Paun; Challice Bonifant; W. Brian Dalton; Lukasz P. Gondek; Alison R. Moliterno; Mark J. Levis; Gabriel Ghiaur; Richard J. Jones

doi:10.1126/sciadv.abl8952

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

Theodoros Karantanos, Patric Teodorescu, Brandy Perkins, Ilias Christodoulou, Christopher Esteb, Ravi Varadhan, Eric Helmenstine, Trivikram Rajkhowa, Bogdan C. Paun, Challice Bonifant, W. Brian Dalton, Lukasz P. Gondek, Alison R. Moliterno, Mark J. Levis, Gabriel Ghiaur, Richard J. Jones

School of Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	eabl8952
Journal	Science Advances
Volume	8
Issue number	7
DOIs	https://doi.org/10.1126/sciadv.abl8952
State	Published - Feb 2022

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Karantanos, T., Teodorescu, P., Perkins, B., Christodoulou, I., Esteb, C., Varadhan, R., Helmenstine, E., Rajkhowa, T., Paun, B. C., Bonifant, C., Dalton, W. B., Gondek, L. P., Moliterno, A. R., Levis, M. J., Ghiaur, G., & Jones, R. J. (2022). The role of the atypical chemokine receptor CCRL2 in myelodysplastic syndrome and secondary acute myeloid leukemia. Science Advances, 8(7), Article eabl8952. https://doi.org/10.1126/sciadv.abl8952

Karantanos, T, Teodorescu, P, Perkins, B, Christodoulou, I, Esteb, C, Varadhan, R, Helmenstine, E, Rajkhowa, T, Paun, BC, Bonifant, C , Dalton, WB , Gondek, LP, Moliterno, AR, Levis, MJ , Ghiaur, G & Jones, RJ 2022, 'The role of the atypical chemokine receptor CCRL2 in myelodysplastic syndrome and secondary acute myeloid leukemia', Science Advances, vol. 8, no. 7, eabl8952. https://doi.org/10.1126/sciadv.abl8952

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

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.",

author = "Theodoros Karantanos and Patric Teodorescu and Brandy Perkins and Ilias Christodoulou and Christopher Esteb and Ravi Varadhan and Eric Helmenstine and Trivikram Rajkhowa and Paun, {Bogdan C.} and Challice Bonifant and Dalton, {W. Brian} and Gondek, {Lukasz P.} and Moliterno, {Alison R.} and Levis, {Mark J.} and Gabriel Ghiaur and Jones, {Richard J.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).",

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doi = "10.1126/sciadv.abl8952",

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AU - Karantanos, Theodoros

AU - Teodorescu, Patric

AU - Perkins, Brandy

AU - Christodoulou, Ilias

AU - Esteb, Christopher

AU - Varadhan, Ravi

AU - Helmenstine, Eric

AU - Rajkhowa, Trivikram

AU - Paun, Bogdan C.

AU - Bonifant, Challice

AU - Dalton, W. Brian

AU - Gondek, Lukasz P.

AU - Moliterno, Alison R.

AU - Levis, Mark J.

AU - Ghiaur, Gabriel

AU - Jones, Richard J.

N1 - Publisher Copyright: Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

PY - 2022/2

Y1 - 2022/2

N2 - 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.

AB - 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.

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

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