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Glucocorticoid Resistant Pediatric Acute Lymphoblastic Leukemia Samples Display Altered Splicing Profile and

Rocco Sciarrillo1, Anna Wojtuszkiewicz2, Irsan E Kooi3

  • 1Amsterdam UMC, Vrije Universiteit Amsterdam, Departments of Pediatric Oncology, Hematology and Medical Oncology, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands.

Cancers
|March 25, 2020
PubMed

Insights

Glucocorticoid resistance in pediatric acute lymphoblastic leukemia (ALL) is linked to altered gene splicing. Targeting these splicing changes may offer a new treatment strategy for resistant leukemia.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Glucocorticoid (GC) resistance significantly impairs chemotherapy response in pediatric acute lymphoblastic leukemia (ALL).
  • The molecular basis of GC resistance in ALL remains largely unknown.
  • Deregulated gene splicing is implicated in various cancers and affects drug sensitivity.

Purpose of the Study:

  • To investigate global splicing profiles in relation to GC resistance in ALL.
  • To explore the potential of splicing modulation as a therapeutic approach for GC-resistant ALL.

Main Methods:

  • RNA-sequencing (RNA-seq) was employed for differential splicing analysis on 38 primary ALL samples.
  • Splicing modulators were tested in GC-resistant ALL cell lines and primary specimens.

Main Results:

  • Distinct splicing landscapes were identified between B-cell precursor (BCP)-ALL and T-ALL subtypes.
  • GC resistance-associated splicing alterations were observed in pathways including RNA processing, GC response, cell survival, apoptosis, cell cycle, and metabolism.
  • GC-resistant ALL cells demonstrated sensitivity to splicing modulators, both independently and in combination with GCs.

Conclusions:

  • Aberrant splicing is significantly associated with GC resistance in pediatric ALL.
  • Splicing modulators represent a promising therapeutic avenue for treating GC-resistant ALL patients.
Keywords:
RNA sequencingSF3B modulatorsalternative splicingglucocorticoid resistancepediatric acute lymphoblastic leukemia

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