Trisomy 13 correlates with RUNX1 mutation and increased FLT3 expression in AML-M0 patients

Leiden University, Leyden, South Holland, Netherlands
Haematologica (Impact Factor: 5.81). 09/2007; 92(8):1123-6. DOI: 10.3324/haematol.11296
Source: PubMed


Of 52 AML-M0 patients studied, 16 presented a RUNX1 mutation (30.8 %) and 8 carried a trisomy 13 (15 %). We found a strong correlation between trisomy 13 and RUNX1 mutations, i.e, 7 out of 8 cases with trisomy 13 carried a mutation in RUNX1 (87.5 %, p<0.00056). Trisomy 13 patients with a RUNX1 mutation showed a 4-fold higher expression of FLT3 mRNA compared to controls, and in a selected number of cases, a higher cell fraction expressing FLT3 and an increase in the number of FLT3 receptors at the cell surface. In conclusion, our results show that trisomy 13 is correlated to RUNX1 mutation and increased FLT3 expression in AML-M0.

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Available from: Alexandra Lind, Oct 09, 2015
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    • "Our findings supported a multiple-hit model of leukemogenesis in AML [40]. Previous studies have shown that RUNX1 mutations frequently coexisted with FLT3-ITD or FLT3-TKD [6], trisomy 13 (the locus of the FLT3 gene), or FLT3 overexpression [27] [28] [29]. We found only one patient harboring both RUNX1 mutation and trisomy 13 and five patients with coexisting RUNX1 and FLT3-ITD mutations. "
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    ABSTRACT: Minimally differentiated acute myeloid leukemia (AML-M0) is a rare subtype of AML with poor prognosis. Although genetic alterations are increasingly reported in AML, the gene mutations have not been comprehensively studied in AML-M0. We aimed to examine a wide spectrum of gene mutations in patients with AML-M0 to determine their clinical relevance. Twenty gene mutations including class I, class II, class III of epigenetic regulators (IDH1, IDH2, TET2, DNMT3A, MLL-PTD, ASXL1, and EZH2), and class IV (tumor suppressor genes) were analyzed in 67 patients with AML-M0. Mutational analysis was performed with polymerase chain reaction–based assays followed by direct sequencing. The most frequent gene mutations from our data were FLT3-ITD/FLT3-TKD (28.4%), followed by mutations in IDH1/IDH2 (28.8%), RUNX1 (23.9%), N-RAS/K-RAS (12.3%), TET2 (8.2%), DNMT3A (8.1%), MLL-PTD (7.8%), and ASXL1 (6.3%). Seventy-nine percent (53/67) of patients had at least one gene mutation. Class I genes (49.3%) were the most common mutated genes, which were mutually exclusive. Class III genes of epigenetic regulators were also frequent (43.9%). In multivariate analysis, old age [hazard ratio (HR) 1.029, 95% confidence interval (CI) 1.013-1.044, P = .001) was the independent adverse factor for overall survival, and RUNX1 mutation (HR 2.326, 95% CI 0.978-5.533, P = .056) had a trend toward inferior survival. In conclusion, our study showed a high frequency of FLT3, RUNX1, and IDH mutations in AML-M0, suggesting that these mutations played a role in the pathogenesis and served as potential therapeutic targets in this rare and unfavorable subtype of AML.
    Neoplasia (New York, N.Y.) 06/2014; 16(6). DOI:10.1016/j.neo.2014.06.002 · 4.25 Impact Factor
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    ABSTRACT: Acquired molecular abnormalities (mutations or chromosomal translocations) of the RUNX1 transcription factor gene are frequent in acute myeloblastic leukemias (AMLs) and in therapy-related myelodysplastic syndromes, but rarely in acute lymphoblastic leukemias (ALLs) and chronic myelogenous leukemias (CMLs). Among 18 BCR-ABL+ leukemias presenting acquired trisomy of chromosome 21, we report a high frequency (33%) of recurrent point mutations (4 in myeloid blast crisis [BC] CML and one in chronic phase CML) within the DNA-binding region of RUNX1. We did not found any mutation in de novo BCR-ABL+ ALLs or lymphoid BC CML. Emergence of the RUNX1 mutations was detected at diagnosis or before the acquisition of trisomy 21 during disease progression. In addition, we also report a high frequency of cryptic chromosomal RUNX1 translocation to a novel recently described gene partner, PRDM16 on chromosome 1p36, for 3 (21.4%) of 14 investigated patients: 2 myeloid BC CMLs and, for the first time, 1 therapy-related BCR-ABL+ ALL. Two patients presented both RUNX1 mutations and RUNX1-PRDM16 fusion. These events are associated with a short survival and support the concept of a cooperative effect of BCR-ABL with molecular RUNX1 abnormalities on the differentiation arrest phenotype observed during progression of CML and in BCR-ABL+ ALL.
    Blood 05/2008; 111(7):3735-41. DOI:10.1182/blood-2007-07-102533 · 10.45 Impact Factor
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