Biology subjects

Rodriguez-Sevilla, J. J.

Publications and source records attributed to Rodriguez-Sevilla, J. J..

3 recordsLinked to original sources

bioRxiv2026

TET2-driven activation of AGO2 links epigenetic remodeling to myeloid commitment and leukemia

DNA methylation dynamics shape hematopoietic differentiation and leukemogenesis; yet how the dioxygenase TET2--frequently mutated in myeloid malignancies--directs lineage-specific regulatory programs remains unclear. Here, we integrated DNA methylation, chromatin accessibility, 3D genome architecture, transcriptional profiling, and TET2 chromatin occupancy to define TET2-dependent control of human myeloid commitment. We found that TET2-bound regulatory regions gain short- and long-range chromatin interactions and that a distinct subset of distal, enhancer-enriched sites undergoes TET2-driven demethylation and activation. Among these, we identified an AGO2 myeloid-specific intragenic enhancer that is frequently hypermethylated in TET2-mutant AML patients. AGO2 expression stratifies patient survival, and AGO2 depletion abrogates leukemic engraftment in vivo. These findings uncover a TET2-AGO2 regulatory axis that integrates epigenetic remodeling, 3D genome reorganization, and leukemic fitness, and they highlight AGO2 as a potential biomarker and therapeutic target in myeloid leukemia.

genomics↗

bioRxiv2023

IL-1B-mediated inflammatory signaling drives ineffective erythropoiesis in early-stage myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a group of incurable hematopoietic stem cell (HSC) neoplasms characterized by peripheral blood cytopenias and a high risk of progression to acute myeloid leukemia. MDS represent the final stage in a continuum of HSCs genetic and functional alterations and are preceded by a premalignant phase, clonal cytopenia of undetermined significance (CCUS). Dissecting the mechanisms of CCUS maintenance may uncover therapeutic targets to delay or prevent malignant transformation. Here, we demonstrate that DNMT3A and TET2 mutations, the most frequent mutations in CCUS, induce aberrant HSCs differentiation towards the myeloid lineage at the expense of erythropoiesis by upregulating IL-1{beta}-mediated inflammatory signaling and that canakinumab rescues red blood cell transfusion dependence in early-stage MDS patients with driver mutations in DNMT3A and TET2. This study illuminates the biological landscape of CCUS and offers an unprecedented opportunity for MDS intervention during its initial phase, when expected survival is prolonged.

cancer biology↗

bioRxiv2023

Targeting MCL1-driven anti-apoptotic pathways to overcome hypomethylating agent resistance in RAS-mutated chronic myelomonocytic leukemia

RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Using single-cell, multi-omics technologies, we sought to dissect the biological mechanisms underlying the initiation and progression of RAS pathway-mutated CMML. We found that RAS pathway mutations induced the transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs), which underwent proliferation and monocytic differentiation in response to cell-intrinsic and -extrinsic inflammatory signaling that also impaired immune cells functions. HSPCs expanded at disease progression and relied on the NF-KB pathway effector MCL1 to maintain their survival, which explains why patients with RAS pathway- mutated CMML do not benefit from BCL2 inhibitors such as venetoclax. Our study has implications for developing therapies to improve the survival of patients with RAS pathway- mutated CMML.

cancer biology↗