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| Home > Publications database > FLT3-ITD Induces CMTM6 and Enhances Immune Escape in Acute Myeloid Leukemia. |
| Home > Publications database > FLT3-ITD Induces CMTM6 and Enhances Immune Escape in Acute Myeloid Leukemia. |
| Journal Article | DKFZ-2026-00127 |
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2026
AACR
Philadelphia, Pa.
Abstract: FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutations are frequent in acute myeloid leukemia (AML) and are associated with a high risk of relapse. CKLF-like MARVEL transmembrane domain containing member 6 (CMTM6) stabilizes PD-L1 surface expression and modulates tumor immunity in solid cancer. In this study, we found a role for FLT3-induced CMTM6 in hematologic malignancies. FLT3 drove CMTM6 and PD-L1 expression in AML cells, whereas FLT3 inhibition reduced expression of CMTM6 and PD-L1. In three distinct allogeneic hematopoietic cell transplantation mouse models, transplantation of Cmtm6-deficient FLT3-ITD+ leukemia cells resulted in prolonged survival, reduced leukemia burden, enhanced T-cell effector function, and decreased expression of T-cell exhaustion markers compared with Cmtm6-proficient FLT3-ITD+ leukemia cells. Furthermore, combination therapy with anti-PD-L1 and tandutinib significantly improved survival, suppressed leukemia cell expansion, and augmented the anti-leukemia T-cell response in mice bearing FLT3-ITD+ leukemia. Mechanistically, protein-protein interaction of FLT3 and CMTM6 within their transmembrane domains, which was not phosphorylation dependent, enhanced CMTM6 stability in leukemia cells, whereas FLT3-ITD did not increase CMTM6 and PD-L1 expression at the RNA level. Furthermore, CMTM6 upregulation and protein interaction with FLT3 were validated in primary leukemia cells from two independent cohorts of patients with FLT3-ITD+ AML. Collectively, these findings uncover FLT3-mediated stabilization of CMTM6 in AML cells, which results in enhanced PD-L1 cell surface expression and leukemia immune escape.Activation of the CMTM6/PD-L1 axis in FLT3-ITD-driven acute myeloid leukemia mediates immunosuppression, providing the basis for potential inhibition of this pathway to harness antitumor immunity.
Keyword(s): Animals (MeSH) ; Humans (MeSH) ; Leukemia, Myeloid, Acute: immunology (MeSH) ; Leukemia, Myeloid, Acute: genetics (MeSH) ; Leukemia, Myeloid, Acute: pathology (MeSH) ; Leukemia, Myeloid, Acute: drug therapy (MeSH) ; fms-Like Tyrosine Kinase 3: genetics (MeSH) ; fms-Like Tyrosine Kinase 3: metabolism (MeSH) ; MARVEL Domain-Containing Proteins: genetics (MeSH) ; MARVEL Domain-Containing Proteins: metabolism (MeSH) ; Mice (MeSH) ; Tumor Escape (MeSH) ; Chemokines: genetics (MeSH) ; Chemokines: metabolism (MeSH) ; B7-H1 Antigen: metabolism (MeSH) ; B7-H1 Antigen: antagonists & inhibitors (MeSH) ; B7-H1 Antigen: genetics (MeSH) ; Myelin Proteins: genetics (MeSH) ; Myelin Proteins: metabolism (MeSH) ; Cell Line, Tumor (MeSH) ; Tandem Repeat Sequences (MeSH) ; Mutation (MeSH) ; fms-Like Tyrosine Kinase 3 ; MARVEL Domain-Containing Proteins ; CMTM6 protein, human ; FLT3 protein, human ; Chemokines ; B7-H1 Antigen ; Myelin Proteins ; CD274 protein, human
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