An alternative CYB5A transcript is expressed in aneuploid ALL and enriched in relapse

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a heterogeneous cancer with poor outcomes in relapsed adult patients.
• The genetic underpinnings of relapse in aneuploid subtypes like near haploid (NH) and high hyperdiploid (HeH) BCP-ALL remain poorly understood.
• Identifying novel genetic alterations is crucial for understanding BCP-ALL relapse.

Purpose of the Study:

• To investigate genetic alterations in matched initial diagnosis-relapse (ID-REL) BCP-ALL samples.
• To identify novel genetic alterations contributing to relapse in BCP-ALL, particularly in NH and HeH subtypes.
• To characterize the functional role of identified alterations in BCP-ALL.

Main Methods:

• RNA sequencing analysis of matched ID-REL BCP-ALL cohorts.
• Validation of findings in an independent cohort of adult BCP-ALL samples.
• Functional studies involving overexpression of the novel CYB5Aalt transcript in NALM-6 cells, followed by RNA sequencing and cell death/viability assays.

Main Results:

• Identification of CYB5Aalt, a novel alternative transcript of CYB5A, with increased expression in relapsed BCP-ALL.
• CYB5Aalt expression was specific to the NH and HeH BCP-ALL subtypes.
• Overexpression of CYB5Aalt in cell lines altered transcriptional programs, decreased wildtype CYB5A expression, and conferred drug resistance, suggesting a role in BCL2-mediated apoptosis.

Conclusions:

• CYB5Aalt is a frequent secondary genetic event in relapsed NH and HeH BCP-ALL.
• CYB5Aalt is a potential contributor to therapy resistance in these specific BCP-ALL subtypes.
• The findings provide initial evidence for CYB5Aalt's functional role in BCL2-mediated apoptosis, offering a new therapeutic target.