CCRL2 promotes the interferon-γ signaling response in myeloid neoplasms with erythroid differentiation and mutated .

Unlabelled: Patients with myeloid neoplasms with loss-of-function mutations and erythroid differentiation have poor outcomes, and a better understanding of disease biology is required. Upregulation of interferon-γ (IFN-γ) signaling has been associated with acute myeloid leukemia (AML) progression and chemotherapy resistance, but its drivers remain unclear. In this study, we found that the surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in AML with erythroid differentiation and mutations compared to other AML subtypes and healthy hematopoietic cells. The knockout (KO) of CCRL2 suppressed erythroleukemia growth and . Further proteomics and transcriptomics analysis revealed IFN-γ signaling response as the top CCRL2-regulated pathway in erythroleukemia. Our mechanistic studies support direct CCRL2 driven IFN-γ signaling independent of exogenous IFN-γ, through phosphorylation of STAT1, via JAK2-dependent and independent mechanisms. CCRL2/IFN-γ signaling is upregulated in erythroid leukemias, and mutated AML without concurrent increase of IFN-γ secretion in the bone marrow microenvironment and is directly induced by KO. Finally, CCRL2/IFN-γ signaling is associated with the transformation of pre-leukemic single-hit clones to multi-hit mutated AML, increased resistance to venetoclax and worse survival in AML. Overall, our findings support that CCRL2 is an essential driver of cell-autonomous IFN-γ signaling response in myeloid neoplasms with erythroid differentiation and mutations and highlight CCRL2 as a relevant novel target for these neoplasms.

One Sentence Summary: CCRL2 is overexpressed in AML with loss-of-function mutations and erythroid differentiation and promotes IFN-γ signaling response via a cell-intrinsic mechanism.