Clinical significance of RAS pathway alterations in pediatric acute myeloid leukemia

Haematologica. 2022 Mar 1;107(3):583-592. doi: 10.3324/haematol.2020.269431.

Abstract

RAS pathway alterations have been implicated in the pathogenesis of various hematological malignancies. However, their clinical relevance in pediatric acute myeloid leukemia (AML) is not well characterized. We analyzed the frequency, clinical significance, and prognostic relevance of RAS pathway alterations in 328 pediatric patients with de novo AML. RAS pathway alterations were detected in 80 (24.4%) of 328 patients: NF1 (n=7, 2.1%), PTPN11 (n=15, 4.6%), CBL (n=6, 1.8%), NRAS (n=44, 13.4%), KRAS (n=12, 3.7%). Most of these alterations in the RAS pathway were mutually exclusive also together with other aberrations of signal transduction pathways such as FLT3-ITD (P=0.001) and KIT mutation (P=0.004). NF1 alterations were frequently detected in patients with complex karyotype (P=0.031) and were found to be independent predictors of poor overall survival (OS) in multivariate analysis (P=0.007). At least four of seven patients with NF1 alterations had biallelic inactivation. NRAS mutations were frequently observed in patients with CBFB-MYH11 and were independent predictors of favorable outcomes in multivariate analysis (OS, P=0.023; event-free survival [EFS], P=0.037). Patients with PTPN11 mutations more frequently received stem cell transplantation (P=0.035) and showed poor EFS than patients without PTPN11 mutations (P=0.013). Detailed analysis of RAS pathway alterations may enable a more accurate prognostic stratification of pediatric AML and may provide novel therapeutic molecular targets related to this signal transduction pathway.

MeSH terms

  • Child
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Leukemia, Myeloid, Acute* / diagnosis
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / therapy
  • Mutation
  • Prognosis

Grants and funding

Funding: This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Health, Labor and Welfare of Japan (15H05909), a grant for project for development of innovative research on cancer therapeutics (PDIRECT) from the Japanese Agency for Medical Research and Development (AMED; JP16ck0106064, JP 19ck0106329), the Japanese Society for the Promotion of Science (KAKENHI grants 17K10130, 18H06234, 19K21333, 20K08744), a research grant from the Japanese Society of Hematology, and the Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics.