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Epigenetic Modeling of Jumping Translocations of 1q Heterochromatin in Acute Myeloid Leukemia After 5'-Azacytidine Treatment. | LitMetric

AI Article Synopsis

  • Jumping translocations (JT), linked to disease progression in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), involve the movement of a tri-tetra-somic 1q chromosome to various other chromosomes.
  • Research showed that in patients with SRSF2 mutations, JT was associated with changes in DNA methylation during treatment with 5'-azacytidine (AZA), revealing significant shifts in the methylome and impacting various biological pathways.
  • The study highlighted that epigenetic modifications, including changes in DNA methylation and specific signaling pathways like PI3K/AKT and MAPK, play a crucial role in the progression of myeloid neoplasms associated with

Article Abstract

Jumping translocations (JT) are rare cytogenetic abnormalities associated with progression in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Typically, a tri-tetra-somic 1q chromosome is translocated to two or more recipient chromosomes. In multiple myeloma JT were shown to originate after DNA demethylation and decondensation. Using epigenomics, we investigated sequential samples in an SRSF2-mutated MDS and AML cohort with normal karyotype at diagnosis and 1qJT at disease evolution after 5'-azacytidine (AZA). 1qJT breakpoints fell within repetitive DNA at both 1q12 and the translocation partners, namely acrocentrics n. 14, 15, 21, and 22, chromosome 16, and chromosome Y. The global methylome at diagnosis showed hypermethylation at 61% of the differentially methylated regions (DMRs), followed by hypomethylation at 80% of DMRs under AZA, mostly affecting pathways related to immune system, chromatin organization, chromosome condensation, telomere maintenance, rRNA, and DNA repair. At disease evolution, a shift toward hypermethylation, intronic enhancers enrichment and epigenetic involvement of the PI3K/AKT and MAPK signaling emerged. In particular, AKT1 phosphorylation behaved as a hallmark of the progression. Overall, we provided new insights on the characterization of 1qJT in SRSF2-mutated myeloid neoplasms and first showed that epigenetics is a powerful tool to investigate the molecular landscape of repetitive DNA rearrangements.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602642PMC
http://dx.doi.org/10.1002/gcc.70013DOI Listing

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