Effects of NRAS Mutations on Leukemogenesis and Targeting of Children With Acute Lymphoblastic Leukemia

Through the advancements in recent decades, childhood acute lymphoblastic leukemia (ALL) is gradually becoming a highly curable disease. However, the truth is there remaining relapse in similar to 15% of ALL cases with dismal outcomes. RAS mutations, in particular NRAS mutations, were predominant mutations affecting relapse susceptibility. KRAS mutations targeting has been successfully exploited, while NRAS mutation targeting remains to be explored due to its complicated and compensatory mechanisms. Using targeted sequencing, we profiled RAS mutations in 333 primary and 18 relapsed ALL patients and examined their impact on ALL leukemogenesis, therapeutic potential, and treatment outcome. Cumulative analysis showed that RAS mutations were associated with a higher relapse incidence in children with ALL. In vitro cellular assays revealed that about one-third of the NRAS mutations significantly transformed Ba/F3 cells as measured by IL3-independent growth. Meanwhile, we applied a high-throughput drug screening method to characterize variable mutation-related candidate targeted agents and uncovered that leukemogenic-NRAS mutations might respond to MEK, autophagy, Akt, EGFR signaling, Polo-like Kinase, Src signaling, and TGF-beta receptor inhibition depending on the mutation profile.

Automated summary

Through targeted sequencing and high-throughput drug screening, we studied the role of RAS mutations in ALL patients and found that RAS mutations were associated with a higher relapse incidence in children with ALL. Among these mutations, NRAS mutations had a higher leukemogenic potential and might exhibit different responsiveness to inhibition of multiple signaling pathways.