Landscape and Clinicopathologic Features of Ras Pathway Mutations in Chronic Myelomonocytic Leukemia

Authors

Guillermo Montalban-Bravo
Sanam Loghavi
Ziyi Li
Kelly Chien
Rashmi Kanagal-Shamanna
Alex Bataller
Anuya Natu
Mark Gurney
Alexandre Bazinet
Danielle Hammond
Koji Sasaki
Gautam Borthakur
Mahesh Swaminathan
Courtney DiNardo
Tapan Kadia
Farhad Ravandi
Naval Daver
Nicholas Short
Naveen Pemmaraju
Ghayas Issa
Terra L Lasho
Christy M Finke
Aref Al-Kali
Clifford Csizmar
Hassan Alkhateeb
Naseema Gangat
Abhishek A Mangaonkar
Carlos Bueso-Ramos
Ayalew Tefferi
Hagop Kantarjian
Guillermo Garcia-Manero
Mrinal M Patnaik

Language

English

Publication Date

10-14-2025

Journal

Blood Advances

DOI

10.1182/bloodadvances.2025016529

PMID

40644618

PMCID

PMC12848361

PubMedCentral® Posted Date

7-15-2025

PubMedCentral® Full Text Version

Post-print

Abstract

RAS pathway (RASp) mutations induce proliferative features, and promote transformation in chronic myelomonocytic leukemia (CMML). However, the unique clonal landscape and hierarchy of distinct RASp mutations remain unexplored. To characterize the landscape, architecture, and implications of unique RASp mutations in CMML, we evaluated a cohort of 814 patients with CMML. We identified 461 RASp mutations among 342 patients (42%). N/KRAS and CBL mutations were the most common, frequently involved the P-loop or RING domains, respectively, and frequently appeared as dominant events (63% and 65%, respectively). BRAF, NF1, and PTPN11 mutations spanned throughout the gene structure, and frequently appeared as subclonal events (75%, 64%, and 59%, respectively). CBL mutations frequently occurred in codominance with SRSF2 and multihit TET2, and were enriched for KIT mutations. PTPN11 mutations more frequently co-occurred with SETBP1 and DNMT3A mutations, and were infrequently codominant with TET2 or ASXL1. RASp mutations predicted for shorter overall survival (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.15-2.07; P = .0075) and leukemia-free survival (LFS; HR, 1.67; 95% CI, 1.26-2.20; P = .0011), influenced outcomes of myelodysplastic and TET2 mutant CMML, and cooperated with IDH2 and RUNX1 mutations to induce shorter LFS. These data set the bases for refined genomic classifications of CMML, and underscore the need to develop RAS-directed therapies for patients with CMML.

Keywords

Humans, Leukemia, Myelomonocytic, Chronic, Mutation, Male, Female, Aged, Middle Aged, Aged, 80 and over, ras Proteins, Signal Transduction, Adult

Published Open-Access

yes

Recommended Citation

Montalban-Bravo, Guillermo; Loghavi, Sanam; Li, Ziyi; et al., "Landscape and Clinicopathologic Features of Ras Pathway Mutations in Chronic Myelomonocytic Leukemia" (2025). Faculty, Staff and Student Publications. 5566.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5566