AI Article Synopsis

  • Acute myeloid leukemia (AML) is a serious blood cancer with few treatment options and a high chance of coming back after chemotherapy.
  • Researchers studied N-myristoylation, a protein modification linked to cancer cell survival, and found that the level of N-myristoyltransferase 2 (NMT2) can indicate patient outcomes.
  • They tested a drug called zelenirstat, which inhibits myristoylation, and found it caused cancer cell death and reduced leukemia in models, suggesting it could be an effective new treatment for AML patients with poor prognoses.

Article Abstract

Acute myeloid leukemia (AML) is a hematological malignancy with limited treatment options and a high likelihood of recurrence after chemotherapy. We studied N-myristoylation, the myristate modification of proteins linked to survival signaling and metabolism, as a potential therapeutic target for AML. N-myristoylation is catalyzed by two N-myristoyltransferases (NMTs), NMT1 and NMT2, with varying expressions in AML cell lines and patient samples. We identified NMT2 expression as a marker for AML patient survival, and low NMT2 expression was associated with poor outcomes. We used the first-in-class pan-NMT inhibitor, zelenirstat, to investigate the role of N-myristoylation in AML. Zelenirstat effectively inhibits myristoylation in AML cell lines and patient samples, leading to degradation of Src family kinases (SFKs), induction of endoplasmic reticulum (ER) stress, apoptosis, and cell death. Zelenirstat was well tolerated in vivo and reduced the leukemic burden in an ectopic AML cell line and in multiple orthotopic AML patient-derived xenograft models. The leukemia stem cell (LSC)-enriched fractions of the hierarchical OCI-AML22 model were highly sensitive to myristoylation inhibition. Zelenirstat also impairs mitochondrial complex I and oxidative phosphorylation, which are critical for LSC survival. These findings suggest that targeting N-myristoylation with zelenirstat represents a novel therapeutic approach for AML, with promise in patients with currently poor outcomes.

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Source
http://dx.doi.org/10.1158/1535-7163.MCT-24-0307DOI Listing

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