Targeting splicing for hematological malignancies therapy.

Area of Science:

• Molecular Biology
• Hematology
• Cancer Research

Background:

• Alterations in messenger RNA (mRNA) splicing are critical in leukemic cells, impacting cellular functions and conferring advantages like proliferation and drug resistance.
• Splicing factors, frequently mutated in blood neoplasms, regulate mRNA processing, and their dysregulation contributes to leukemogenesis.

Purpose of the Study:

• To review the mechanisms of mRNA processing and the role of splicing factors in blood cancers.
• To summarize alternative splicing events that lead to resistance against targeted therapies and immunotherapies.
• To discuss the functional consequences of specific mis-spliced variants in leukemia and novel therapeutic strategies.

Main Methods:

• Literature review focusing on mRNA processing, splicing factor mutations, and alternative splicing in leukemia.
• Analysis of functional consequences of specific aberrant splicing events and their role in therapeutic resistance.
• Summary of current and emerging therapeutic strategies targeting aberrant splicing.

Main Results:

• Aberrantly spliced isoforms in leukemia can promote proliferation, evade apoptosis, alter metabolism, affect cell signaling, and drive drug resistance.
• Specific mis-spliced variants (e.g., CD19-∆ex2, BCR-ABL^35INS, BIM-γ) have defined functional consequences in leukemic cells.
• Novel therapeutic approaches, including small-molecule splicing modulators and splice-switching oligonucleotides, show promise for correcting aberrant splicing.

Conclusions:

• Disrupted splicing is a key driver in hematological malignancies, contributing to disease progression and treatment failure.
• Targeting aberrant splicing pathways presents a promising therapeutic avenue for leukemia.
• Emerging combination therapies hold potential for treating hematological disorders with disrupted splicing patterns.