Transcriptional regulatory program controlled by MYB in T-cell acute lymphoblastic leukemia

Area of Science:

• Molecular Biology
• Hematology
• Oncology

Background:

• The transcription factor MYB is often overexpressed in T-cell acute lymphoblastic leukemia (T-ALL).
• MYB is implicated in regulating genes vital for T-ALL development and progression.

Purpose of the Study:

• To investigate the role of MYB in T-ALL pathogenesis.
• To identify specific MYB isoforms and their functions in T-ALL cells.
• To elucidate the gene regulatory network controlled by MYB in T-ALL.

Main Methods:

• Integrative analysis to identify MYB isoforms.
• Utilized dTAG-mediated protein degradation for rapid MYB depletion.
• Analyzed gene expression changes and classified responses into early and late kinetics.

Main Results:

• A long MYB isoform (ENST00000367814.8) is predominantly expressed and promotes T-ALL cell proliferation.
• MYB depletion rapidly impacts numerous genes, categorized as early or late responders.
• Early response genes involved in hematopoiesis (e.g., TAL1, RUNX1, GATA3) showed transient downregulation, suggesting feedback.
• Late response genes, including proliferation-associated genes and TAL1 targets, were continuously downregulated, altering cellular phenotype.

Conclusions:

• MYB is essential for T-ALL pathogenesis, primarily through a long isoform driving proliferation.
• MYB regulates distinct sets of genes with different kinetic responses, indicating complex regulatory mechanisms.
• Understanding MYB's role and regulatory network offers potential therapeutic targets for T-ALL.