BRAF kinase domain mutations are present in a subset of chronic myelomonocytic leukemia with wild-type RAS.
The frequency of RAS mutations in chronic myelomonocytic leukemia (CMML) suggests that activation of the MAPK pathway is important in CMML pathogenesis. Accordingly, we hypothesized that mutations in other members of the MAPK pathway might be overrepresented in RAS(wt) CMML. We performed targeted next generation sequencing analysis on 70 CMML patients with known RAS mutation status. The study group included 37 men and 33 women with a median age of 67.8 years (range, 28-86 years). Forty patients were RAS(wt) and 30 were RAS(mut) ; the latter included KRAS = 17; NRAS = 12; KRAS + NRAS = 1. Five patients (7.1% of total group; 12.5% of RAS(wt) group) with RAS(wt) had kinase domain BRAF mutations. The BRAF mutations were of missense type and involved exon 11 in one patient and exon 15 in four patients. All BRAF(mut) patients had CMML-1 with low-risk cytogenetic findings. Two (40%) of the five patients with BRAF(mut) patients transformed to acute myeloid leukemia during follow-up. In summary, we demonstrate that a subset of patients with RAS(wt) CMML harbors BRAF kinase domain mutations that are potentially capable of activating the MAPK signaling pathway.
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Liping
L
Zhang
Rajesh R
RR
Singh
Keyur P
KP
Patel
Francesco
F
Stingo
Mark
M
Routbort
M James
MJ
You
Roberto N
RN
Miranda
Guillermo
G
Garcia-Manero
Hagop M
HM
Kantarjian
L Jeffrey
LJ
Medeiros
Rajyalakshmi
R
Luthra
Joseph D
JD
Khoury
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000201:enzymology / Q000235:genetics*; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics*
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins