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December 8, 2025BloodOpen Access

Genomic alterations in TET2 and EZH2 serve as critical drivers of clonal malignant evolution in anti-BCMA CAR-T therapy for multiple myeloma.

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Authors

AAAdolfo AlemanALAlessandro Laganà

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Overview

Observations reveal decreased cytokine production and cytotoxic capability in malignant CAR-T cells with TET2 and EZH2 mutations, suggesting implications for treatment safety.

Key Points

  • Investigate genomic alterations in TET2 and EZH2 involved in clonal malignant evolution from anti-BCMA CAR-T therapy.
  • Isolated CAR+ peripheral T-cell lymphoma from patients' blood.
  • Performed single cell sequencing and RNA sequencing on tumor samples.
  • Generated CAR-T cells from healthy donors and the patient for mutational analysis.
  • Characterized functional response via antigen specific stimulation with BCMA expressing cell lines.
  • Identified TET2 and EZH2 mutations associated with clonal hematopoiesis in PTCL after CAR-T therapy.
  • Malignant CAR-T exhibited a 98% reduction in cytotoxic capability compared to pre-therapy controls.
  • EZH2 knockdown in CAR-T cells improved proliferative markers while reducing functional killing capacity by 28%.
  • TET2 knockdown resulted in a 53% decrease in function, with double knock down showing a 67% reduction in cytotoxicity.

Cite This Study

Aleman et al. (2025) studied this question.

synapsesocial.com/papers/69362f364fa91c937236d35bhttps://doi.org/10.1182/blood-2025-3946
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