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December 8, 2025BloodOpen Access

TTLL4 glutamyltransferase is a therapeutic target for NPM1-mutated Acute Myeloid Leukemia

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Authors

HIHumaira IlyasMMMaxim I. MaronJSJeffrey Shabanowitz

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Overview

Knockdown of TTLL4 increases CD11b expression and alters gene expression in NPM1-mutated AML, suggesting a novel therapeutic strategy.

Key Points

  • To evaluate the role of TTLL4 in NPM1-mutated Acute Myeloid Leukemia and assess its potential as a therapeutic target.
  • Knockdown of TTLL4 using CRISPR-Cas9 and shRNA in NPM1-mutated OCI-AML3 cells
  • Mass spectrometry analysis on NPM1 variants
  • RNA sequencing after TTLL4 knockdown
  • Mouse models to assess the impact of Ttll4 deletion on AML progression
  • Identification and testing of small molecule EN7 for TTLL4 inhibition
  • Knockdown of TTLL4 impaired proliferation and promoted myeloid differentiation in OCI-AML3 cells
  • TTLL4 knockdown correlated with increased CD11b expression and changes consistent with neutrophil and monocyte morphology
  • Ttll4 deletion in mouse models led to impaired colony formation in NPM1c+ cells and prolonged survival in recipients
  • EN7 selectively inhibited TTLL4, inducing differentiation effects in NPM1c AML cell lines without affecting wild-type cells

Cite This Study

Ilyas et al. (2025) studied this question.

synapsesocial.com/papers/693624d44fa91c937236d06ehttps://doi.org/10.1182/blood-2025-869
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Disrupting the PA2G4-NPM1 axis induces nucleolar stress in NPM1c AML2025
  2. 2Expression of recombinant human glutamylating TTLLs in human cells leads to differential tubulin glutamylation patterns, with only TTLL6 disrupting microtubule dynamics2026 · 1 citations
  3. 3Targeting the METTL1/m7G axis as a therapeutic strategy in myeloid leukemia2025 · 1 citations
  4. 4The KMT2A-PTD oncoprotein depends on ENL but not menin to drive AML gene expression2025 · 1 citations
  5. 5Pharmacological targeting of CTPS1 elicits macrophage-mediated anti-leukemia immunity2025