Article Dans Une Revue Leukemia Année : 2025

DYRK1A inhibition results in MYC and ERK activation rendering KMT2A-R acute lymphoblastic leukemia cells sensitive to BCL2 inhibition

V S S Abhinav Ayyadevara
John A Chukinas
  • Fonction : Auteur
Joseph P Loftus
  • Fonction : Auteur
Sung June Lee
  • Fonction : Auteur
Anil Kumar
  • Fonction : Auteur
Srividya Swaminathan
Wayne Childers
Huimin Geng
  • Fonction : Auteur
Thomas A Milne
Xianxin Hua
  • Fonction : Auteur
Kathrin M Bernt
Junwei Shi
John D Crispino
Christian Hurtz

Résumé

Unbiased kinome-wide CRISPR screening identified DYRK1A as a potential therapeutic target in KMT2A -rearranged ( KMT2A- R) B-acute lymphoblastic leukemia (ALL). Mechanistically, we demonstrate that DYRK1A is regulated by the KMT2A fusion protein and affects cell proliferation by regulating MYC expression and ERK phosphorylation. We further observed that pharmacologic DYRK1A inhibition markedly reduced human KMT2A -R ALL cell proliferation in vitro and potently decreased leukemia proliferation in vivo in drug-treated patient-derived xenograft mouse models. DYRK1A inhibition induced expression of the proapoptotic factor BIM and reduced the expression of BCL-XL, consequently sensitizing KMT2A -R ALL cells to BCL2 inhibition. Dual inhibition of DYRK1A and BCL2 synergistically decreased KMT2A -R ALL cell survival in vitro and reduced leukemic burden in mice. Taken together, our data establishes DYRK1A as a novel therapeutic target in KMT2A -R ALL and credential dual inhibition of DYRK1A and BCL2 as an effective translational therapeutic strategy for this high-risk ALL subtype.

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hal-05175869 , version 1 (22-07-2025)

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V S S Abhinav Ayyadevara, Gerald Wertheim, Shikha Gaur, John A Chukinas, Joseph P Loftus, et al.. DYRK1A inhibition results in MYC and ERK activation rendering KMT2A-R acute lymphoblastic leukemia cells sensitive to BCL2 inhibition. Leukemia, 2025, 39 (5), pp.1078-1089. ⟨10.1038/s41375-025-02575-w⟩. ⟨hal-05175869⟩
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