CCRL2 promotes the interferon-γ signaling response in myeloid neoplasms with erythroid differentiation and mutated TP53
Patients with myeloid neoplasms with loss-of-function TP53 mutations and erythroid differentiation have poor outcomes, and a better understanding of disease biology is required. Upregulation of interferon-{gamma} (IFN-{gamma}) 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 TP53 mutations compared to other AML subtypes and healthy hematopoietic cells. The knockout (KO) of CCRL2 suppressed erythroleukemia growth in vitro and in vivo. Further proteomics and transcriptomics analysis revealed IFN-{gamma} signaling response as the top CCRL2-regulated pathway in erythroleukemia. Our mechanistic studies support direct CCRL2 driven IFN-{gamma} signaling independent of exogenous IFN-{gamma}, through phosphorylation of STAT1, via JAK2-dependent and independent mechanisms. CCRL2/IFN-{gamma} signaling is upregulated in erythroid leukemias, and TP53 mutated AML without concurrent increase of IFN-{gamma} secretion in the bone marrow microenvironment and is directly induced by TP53 KO. Finally, CCRL2/IFN-{gamma} signaling is associated with the transformation of pre-leukemic single-hit TP53 clones to multi-hit TP53 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-{gamma} signaling response in myeloid neoplasms with erythroid differentiation and TP53 mutations and highlight CCRL2 as a relevant novel target for these neoplasms. One Sentence SummaryCCRL2 is overexpressed in AML with loss-of-function TP53 mutations and erythroid differentiation and promotes IFN-{gamma} signaling response via a cell-intrinsic mechanism.