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SETD5 regulates leukemic initiation and infiltration in T-cell acute lymphoblastic leukemia
Mingyue Hao1, Yujie Bian2, Mengke Li2
1Haihe Laboratory of Cell Ecosystem, Tianjin Medical University, Tianjin, China.
Experimental Cell Research
|August 13, 2026
Summary
SET domain-containing 5 (SETD5) promotes T-cell acute lymphoblastic leukemia (T-ALL) by regulating cell migration and infiltration. SETD5 depletion impairs leukemia initiation and progression, highlighting its potential as a therapeutic target in T-ALL.
Area of Science:
- Hematology
- Oncology
- Epigenetics
Background:
- T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer driven by epigenetic dysregulation.
- SET domain-containing 5 (SETD5) lacks methyltransferase activity and influences nonenzymatic functions.
- SETD5's role in T-ALL pathogenesis is currently undefined, despite its involvement in normal hematopoiesis.
Purpose of the Study:
- To investigate the role of SETD5 in the initiation and progression of T-cell acute lymphoblastic leukemia (T-ALL).
- To elucidate the molecular mechanisms by which SETD5 influences T-ALL development.
- To explore the therapeutic potential of targeting SETD5 in T-ALL.
Main Methods:
- Utilized ICN1-driven murine T-ALL models (Vav-Cre;Setd5fl/fl and Mx1-Cre;Setd5fl/fl) for genetic ablation studies.
- Performed transplantation assays to evaluate the impact of Setd5 depletion on leukemia burden and survival.
- Conducted transcriptomic profiling of Setd5-deficient T-ALL cells and validated key gene expression changes using RT-qPCR in human T-ALL cell lines (Jurkat, MOLT-4).
Main Results:
- Genetic ablation of Setd5 significantly impaired T-ALL initiation and progression in murine models.
- Setd5 depletion reduced leukemia burden, prolonged survival, and decreased leukemic infiltration in transplantation assays.
- Setd5 deficiency led to the repression of genes involved in cell migration, motility, and cytoskeletal organization, including Plxnb2, Mmp14, Ceacam1, and Clstn1.
- SETD5 knockdown in human T-ALL cell lines markedly reduced proliferation and migration.
Conclusions:
- SETD5 plays a crucial role in promoting T-ALL progression by regulating transcriptional programs essential for leukemic cell migration and infiltration.
- The findings identify SETD5 as a significant contributor to T-ALL pathogenesis.
- SETD5-associated transcriptional pathways represent potential therapeutic vulnerabilities for T-ALL treatment.
