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bioRxiv · 10.1101/2021.07.29.454394

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

KARANTANOS, T.·Teodorescu, P.·Perkins, B.·Christodolou, I.·Esteb, C.·Varadhan, R.·Helmenstine, E.·Rajkhowa, T.·Paun, B.·Bonifant, C.·Dalton, W. B.·Gondek, L. P.·Moliterno, A. R.·Levis, M. J.·Ghiaur, G.·Jones, R. J.
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Abstract

The identification of new molecular pathways supporting the growth of myelodysplastic syndrome (MDS) stem and progenitor cells is needed to understand clinical variation and develop targeted therapies. Within myeloid malignancies, men have worse outcomes compared to women, suggesting male sex hormone driven effects in malignant hematopoiesis. The androgen receptor promotes the expression of five granulocyte-colony factor receptor regulated genes. Among them, CCRL2 encodes an atypical chemokine receptor that regulates cytokine signaling in differentiated granulocytes but its role in myeloid malignancies is unknown. Our study revealed that CCRL2 is upregulated in stem and progenitor cells from patients with MDS and secondary acute leukemia. CCRL2 knockdown suppressed the growth and clonogenicity of MDS92 and MDS-L cells in vitro and in vivo. Moreover, CCRL2 knockdown significantly suppressed the phosphorylation of JAK2, STAT3, and STAT5 in MDS cells. CCRL2 co-precipitated with JAK2 and its suppression decreased the interaction of JAK2 with STAT proteins. Cell lines expressing JAK2V617F showed less effect of CCRL2 knockdown on growth and clonogenicity compared to those expressing wild type. However, the selective JAK2 inhibitor fedratinib potentiated the effects of CCRL2 knockdown in MDS and leukemia cells expressing both wild type JAK2 and JAK2V617F. In conclusion, our results implicate CCRL2 as a mediator of MDS and secondary acute leukemia cell growth, in part through JAK2/STAT signaling.

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KARANTANOS, T., Teodorescu, P., Perkins, B., Christodolou, I., Esteb, C., Varadhan, R., Helmenstine, E., Rajkhowa, T., Paun, B., Bonifant, C., Dalton, W. B., Gondek, L. P., Moliterno, A. R., Levis, M. J., Ghiaur, G., Jones, R. J.. 2021-07-30. The role of the atypical chemokine receptor CCRL2 in myelodysplastic syndrome and secondary acute myeloid leukemia. https://doi.org/10.1101/2021.07.29.454394

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