DNA hypomethylation and epigenetic reprogramming

Current understanding

To be populated as evidence accumulates.

Evidence log

• 2026-09-04 — A Phase I/II Study of Trametinib and Azacitidine for Patients With Newly Diagnosed Juvenile Myelomonocytic Leukemia: cross-connection with erk-mapk-signaling-mpn: Trametinib + azacitidine in JMML echoes the ASTX029 + ASTX727 design, reinforcing a recurring therapeutic pairing of MAPK-cascade inhibition with hypomethylating agents in RAS-pathway myeloid neoplasms. (novelty: 3)
• 2026-08-01 — Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A Phase I Dose-Escalation Study of Navitoclax, Venetoclax, and Decitabine.: cross-connection with bcl2-bclxl-dual-inhibition-apoptosis-mpn: Decitabine-induced hypomethylation is combined with dual BCL-2/BCL-xL inhibition, suggesting synergy between epigenetic reprogramming and apoptotic priming in advanced myeloid disease. (novelty: 3)
• 2026-07-09 — Glutamate accumulation in myelofibrosis microenvironment rewires mesenchymal stromal cells metabolic and epigenetic profiles.: Fumarate accumulation downstream of glutamate/mGluR5 signaling in MF-associated MSCs is proposed to drive epigenetic remodeling (via oncometabolite-mediated inhibition of α-KG-dependent dioxygenases), extending epigenetic reprogramming mechanisms beyond hematopoietic cells to the stromal compartment. (novelty: 5)
• 2026-07-23 — DNMT3A and TET2 Mutations are Associated With Both Venous Thrombosis and Major Bleeding in Patients With Polycythemia Vera and Essential Thrombocythemia.: Clinical association study finds mutations in DNA methylation regulators DNMT3A and TET2 track with both thrombosis and bleeding in PV/ET, suggesting that epigenetic-regulator loss-of-function has downstream hemostatic consequences distinct from its role in clonal expansion. (novelty: 3)
• 2026-07-01 — Phase I Trial of Pacritinib in Combination With Venetoclax and Azacitidine for the Treatment of Accelerated and Blast Phase Myeloproliferative Neoplasms: Pacritinib + venetoclax + azacitidine phase I in AP/BP MPN layers HMA-driven DNA hypomethylation with BCL-2 inhibition and JAK/IRAK1 blockade, extending the HMA-backbone combination portfolio into a triple regimen for advanced-phase MPN. (novelty: 4)
• 2026-06-05 — The impact of novel bet inhibitors on the treatment armamentarium of Myelofibrosis.: Review of BET inhibitors in MF broadens the epigenetic-therapy landscape beyond HMAs and LSD1 inhibition to include BET bromodomain readers as a third, transcription-coactivator–level axis of epigenetic reprogramming relevant to MPN. (novelty: 3)
• 2026-05-20 — A Phase 2 Study Evaluating Olutasidenib in Combination With Hypomethylating Agents in Patients With IDH1-mutated Higher-risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Advanced Myeloproliferative Neoplasm: Phase 2 trial pairs olutasidenib (IDH1 inhibitor) with an HMA in IDH1-mutated higher-risk MDS/CMML/advanced MPN, extending the HMA backbone into a mutation-defined combination targeting the IDH1/2-HG–driven epigenetic block alongside DNA hypomethylation. (novelty: 3)
• 2026-01-29 — Guadecitabine and Atezolizumab in Treating Patients With Advanced Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia That Is Refractory or Relapsed: Guadecitabine (next-generation HMA) is being combined with atezolizumab (anti-PD-L1) in R/R MDS/CMML, extending the hypomethylating-agent backbone into checkpoint-inhibitor combinations and testing epigenetic-immunotherapy synergy. (novelty: 3)
• 2026-03-13 — Axatilimab With or Without Azacitidine for the Treatment of Patients With Advanced Phase Myeloproliferative Neoplasms, Myeloproliferative Neoplasm/Myelodysplastic Syndrome Overlap or High Risk Chronic Myelomonocytic Leukemia: cross-connection with csf1r-macrophage-axis-mpn: The axatilimab + azacitidine combination arm couples CSF-1R-mediated macrophage targeting with hypomethylating-agent-driven epigenetic reprogramming, probing potential synergy between innate-immune modulation and DNA methylation in advanced-phase MPN/CMML. (novelty: 4)
• 2026-02-13 — Phase I/II Study of a Combination of Decitabine and Cedazuridine (ASTX727) and ASTX029, an ERK Inhibitor, for Patients With RAS Pathway Mutant Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms: ASTX727 is being combined with the ERK inhibitor ASTX029 in RAS pathway-mutant MDS/MDS-MPN, testing whether DNA hypomethylation synergizes with MAPK pathway blockade in a genomically selected population. (novelty: 4)
• 2026-04-02 — Seclidemstat and Azacitidine for the Treatment of Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia: Seclidemstat + azacitidine phase I/II in MDS/CMML reinforces the dual epigenetic reprogramming paradigm (hypomethylating agent + LSD1 inhibition), now tested with a second LSD1 inhibitor and a different HMA backbone. (novelty: 3)
• 2026-04-28 — A Randomized Study of ASTX727 With or Without Iadademstat in Advanced Myeloproliferative Neoplasms (MPNs): ASTX727 (oral cedazuridine-decitabine) is being tested ± iadademstat in advanced/blast-phase Ph-negative MPN, pairing DNA hypomethylation with LSD1 inhibition as a dual epigenetic reprogramming strategy. (novelty: 4)

Open questions

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