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Updated: May 4, 2026

Preparation of Primary Acute Lymphoblastic Leukemia Cells in Different Cell Cycle Phases by Centrifugal Elutriation
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DYRK1A inhibition results in MYC and ERK activation rendering KMT2A-R acute lymphoblastic leukemia cells sensitive to

V S S Abhinav Ayyadevara1, Gerald Wertheim2, Shikha Gaur1

  • 1Department of Basic Science, Division of Cancer Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.

Leukemia
|March 28, 2025
PubMed

Insights

Dual inhibition of DYRK1A and BCL2 targets KMT2A-rearranged B-acute lymphoblastic leukemia (ALL). This strategy reduces cancer cell proliferation and survival, offering a promising new therapy for high-risk ALL patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Hematology

Background:

  • KMT2A-rearranged (KMT2A-R) B-acute lymphoblastic leukemia (ALL) is a high-risk subtype requiring novel therapeutic strategies.
  • DYRK1A kinase has emerged as a potential therapeutic target in various cancers.

Purpose of the Study:

  • To identify novel therapeutic targets in KMT2A-R ALL using kinome-wide CRISPR screening.
  • To investigate the role of DYRK1A in KMT2A-R ALL pathogenesis and evaluate its therapeutic potential.
  • To assess the efficacy of dual inhibition of DYRK1A and BCL2 in KMT2A-R ALL.

Main Methods:

  • Kinome-wide CRISPR screening to identify therapeutic targets.
  • In vitro and in vivo studies using KMT2A-R ALL cell lines and patient-derived xenograft mouse models.
  • Pharmacologic inhibition of DYRK1A and BCL2, individually and in combination.

Main Results:

  • DYRK1A was identified as a key therapeutic target in KMT2A-R ALL, regulated by the KMT2A fusion protein.
  • DYRK1A inhibition reduced proliferation by regulating MYC expression and ERK phosphorylation.
  • Pharmacologic DYRK1A inhibition decreased leukemia burden in vivo and sensitized cells to BCL2 inhibition.
  • Dual DYRK1A and BCL2 inhibition synergistically reduced KMT2A-R ALL cell survival and leukemic burden.

Conclusions:

  • DYRK1A is a novel therapeutic target for KMT2A-R ALL.
  • Dual inhibition of DYRK1A and BCL2 represents a promising translational therapeutic strategy for high-risk KMT2A-R ALL.

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