title: RUNX1 mutations are frequent in chronic myelomonocytic leukemia and mutations at the C-terminal region might predict acute myeloid leukemia transformation.
abstract: Runt-related transcription factor 1 (RUNX1) is essential for normal hematopoiesis. RUNX1 mutations have rarely been reported in chronic myelomonocytic leukemia (CMML). We examined RUNX1 mutations in 81 patients with CMML at initial diagnosis. Mutational analysis was performed on bone marrow samples by direct sequencing of all reverse transcription PCR products amplified with three primer pairs that cover the entire coding sequences of RUNX1b. Thirty-two RUNX1 mutations were detected in 30 patients (37%); 23 mutants were located in the N-terminal part and 9 in the C-terminal region. The mutations consisted of 9 missense, 1 silent, 7 nonsense and 15 frameshift mutations. Two patients had biallelic heterozygous mutations. There was no difference in overall survival between patients with and without RUNX1 mutations, but a trend of higher risk of acute myeloid leukemia (AML) progression was observed in mutation-positive patients (16/30 vs 17/51, P=0.102), especially in patients with C-terminal mutations (P=0.023). The median time to AML progression was 6.8 months in patients with C-terminal mutations compared with 28.3 months in those without mutations (P=0.022). This study showed for the first time a high frequency of RUNX1 mutations in CMML. C-terminal mutations might be associated with a more frequent and rapid AML transformation.
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan.
authors.forename: M-C
authors.initials: MC
authors.lastname: Kuo
authors.forename: D-C
authors.initials: DC
authors.lastname: Liang
authors.forename: C-F
authors.initials: CF
authors.lastname: Huang
authors.forename: Y-S
authors.initials: YS
authors.lastname: Shih
authors.forename: J-H
authors.initials: JH
authors.lastname: Wu
authors.forename: T-L
authors.initials: TL
authors.lastname: Lin
authors.forename: L-Y
authors.initials: LY
authors.lastname: Shih
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001752:Blast Crisis / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005260:Female; D011905:Genes, ras; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D011379:Prognosis; D017434:Protein Structure, Tertiary; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; C493728:RUNX1 protein, human; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3