[Detection of activating mutations in RAS/RAF/MEK/ERK and JAK/STAT signaling pathways].

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• B-cell acute lymphoblastic leukemia (B-ALL) is a heterogeneous hematologic malignancy.
• Activating mutations in RAS/RAF/MEK/ERK and JAK/STAT signaling pathways are implicated in leukemogenesis.
• Understanding these mutations is crucial for targeted therapy development in adult B-ALL.

Purpose of the Study:

• To investigate the prevalence and clinical significance of activating mutations in NRAS, KRAS, FLT3, JAK2, and CRLF2 genes in adult patients with B-ALL.
• To analyze the association of these mutations with treatment outcomes and minimal residual disease (MRD) status.
• To evaluate these mutations within the context of Russian multicenter clinical trials.

Main Methods:

• A cohort of 119 adult de novo B-ALL patients from Russian multicenter trials were analyzed.
• Molecular analysis included Sanger sequencing for NRAS, KRAS, JAK2, CRLF2 mutations, fragment analysis for FLT3-ITD, and flow cytometry for CRLF2 expression.
• Patients were stratified into BCR-ABL1-negative (n=93) and BCR-ABL1-positive (n=26) groups, with varying treatment protocols and follow-up durations.

Main Results:

• Activating mutations in NRAS, KRAS, and FLT3 were identified in 23.6% of BCR-ABL1-negative B-ALL patients, significantly more frequent than in BCR-ABL1-positive cases.
• Specific mutation frequencies included NRAS (9.7%), KRAS (12.9%), FLT3-ITD (3.5%), JAK2 (3.2%), and CRLF2 overexpression (2.2%).
• No statistically significant differences were observed in demographic, clinical laboratory parameters, long-term therapy results, or MRD achievement rates between patients with and without these mutations.

Conclusions:

• Activating mutations in NRAS, KRAS, FLT3, and JAK2 do not appear to influence long-term therapeutic results or MRD status in adult BCR-ABL1-negative B-ALL patients within these trials.
• The findings suggest that while these mutations are present, their prognostic or predictive value may be limited in this specific patient cohort and treatment setting.
• Further research may be warranted to explore potential targeted therapies or alternative prognostic markers.