Activating mutations remodel the chromatin accessibility landscape to drive distinct regulatory networks in KMT2A-rearranged acute leukemia.

Zhang Q, Falqués-Costa T, Pilheden M, Sturesson H, Ovlund T, Rissler V, Castor A, Marquart HVH, Lausen B, Fioretos T, Hyrenius-Wittsten A, Hagström-Andersson AK

Hemasphere 8 (9) e70006 [2024-09-00; online 2024-09-26]

Activating FLT3 and RAS mutations commonly occur in leukemia with KMT2A-gene rearrangements (KMT2A-r). However, how these mutations cooperate with the KMT2A-r to remodel the epigenetic landscape is unknown. Using a retroviral acute myeloid leukemia (AML) mouse model driven by KMT2A::MLLT3, we show that FLT3 , ITDFLT3 , and N676KNRAS remodeled the chromatin accessibility landscape and associated transcriptional networks. Although the activating mutations shared a common core of chromatin changes, each mutation exhibits unique profiles with most opened peaks associating with enhancers in intronic or intergenic regions. Specifically, G12DFLT3 and N676KNRAS rewired similar chromatin and transcriptional networks, distinct from those mediated by G12DFLT3 . Motif analysis uncovered a role for the AP-1 family of transcription factors in ITDKMT2A::MLLT3 leukemia with FLT3 and N676KNRAS , whereas Runx1 and Stat5a/Stat5b were active in the presence of G12DFLT3 . Furthermore, transcriptional programs linked to immune cell regulation were activated in ITDKMT2A-r AML expressing NRAS or G12DFLT3 , and the expression of NKG2D-ligands on N676KKMT2A-r cells rendered them sensitive to CAR T cell-mediated killing. Human KMT2A-r AML cells could be pharmacologically sensitized to NKG2D-CAR T cells by treatment with the histone deacetylase inhibitor LBH589 (panobinostat) which caused upregulation of NKG2D-ligand levels. Co-treatment with LBH589 and NKG2D-CAR T cells enabled robust AML cell killing, and the strongest effect was observed for cells expressing NRAS . Finally, the results were validated and extended to acute leukemia in infancy. Combined, activating mutations induced mutation-specific changes in the epigenetic landscape, leading to changes in transcriptional programs orchestrated by specific transcription factor networks.G12D

Clinical Genomics Lund [Service]

PubMed 39329074

DOI 10.1002/hem3.70006

Crossref 10.1002/hem3.70006

pmc: PMC11426354
pii: HEM370006