RESUMEN
Monocytic acute myeloid leukemia (AML) responds poorly to current treatments, including venetoclax-based therapy. We conducted in vivo and in vitro CRISPR-Cas9 library screenings using a mouse monocytic AML model and identified SETDB1 and its binding partners (ATF7IP and TRIM33) as crucial tumor promoters in vivo. The growth-inhibitory effect of Setdb1 depletion in vivo is dependent mainly on natural killer (NK) cell-mediated cytotoxicity. Mechanistically, SETDB1 depletion upregulates interferon-stimulated genes and NKG2D ligands through the demethylation of histone H3 Lys9 at the enhancer regions, thereby enhancing their immunogenicity to NK cells and intrinsic apoptosis. Importantly, these effects are not observed in non-monocytic leukemia cells. We also identified the expression of myeloid cell nuclear differentiation antigen (MNDA) and its murine counterpart Ifi203 as biomarkers to predict the sensitivity of AML to SETDB1 depletion. Our study highlights the critical and selective role of SETDB1 in AML with granulo-monocytic differentiation and underscores its potential as a therapeutic target for current unmet needs.
RESUMEN
Immunotherapy has attracted considerable attention as a therapeutic strategy for cancers including acute myeloid leukemia (AML). In this study, we found that the development of several aggressive subtypes of AML is slower in Rag2-/- mice despite the lack of B and T lymphocytes, even compared to the immunologically normal C57BL/6 mice. Furthermore, an orally active p53-activating drug shows stronger antileukemia effect on AML in Rag2-/- mice than C57BL/6 mice. Intriguingly, Natural Killer (NK) cells in Rag2-/- mice are increased in number, highly express activation markers, and show increased cytotoxicity to leukemia cells in a coculture assay. B2m depletion that triggers missing-self recognition of NK cells impairs the growth of AML cells in vivo. In contrast, NK cell depletion accelerates AML progression in Rag2-/- mice. Interestingly, immunogenicity of AML keeps changing during tumor evolution, showing a trend that the aggressive AMLs generate through serial transplantations are susceptible to NK cell-mediated tumor suppression in Rag2-/- mice. Thus, we show the critical role of NK cells in suppressing the development of certain subtypes of AML using Rag2-/- mice, which lack functional lymphocytes but have hyperactive NK cells.
Asunto(s)
Células Asesinas Naturales , Leucemia Mieloide Aguda , Animales , Ratones , Ratones Noqueados , Ratones Endogámicos C57BL , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Linfocitos T , Proteínas de Unión al ADN/genéticaRESUMEN
ATP-dependent chromatin remodeling SWI/SNF complexes exist in three subcomplexes: canonical BAF (cBAF), polybromo BAF (PBAF), and a newly described non-canonical BAF (ncBAF). While cBAF and PBAF regulate fates of multiple cell types, roles for ncBAF in hematopoietic stem cells (HSCs) have not been investigated. Motivated by recent discovery of disrupted expression of BRD9, an essential component of ncBAF, in multiple cancers, including clonal hematopoietic disorders, we evaluate here the role of BRD9 in normal and malignant HSCs. BRD9 loss enhances chromatin accessibility, promoting myeloid lineage skewing while impairing B cell development. BRD9 significantly colocalizes with CTCF, whose chromatin recruitment is augmented by BRD9 loss, leading to altered chromatin state and expression of myeloid-related genes within intact topologically associating domains. These data uncover ncBAF as critical for cell fate specification in HSCs via three-dimensional regulation of gene expression and illuminate roles for ncBAF in normal and malignant hematopoiesis.