Biological Activities of RUNX1 Mutants Predict Secondary Acute Leukemia Transformation from Chronic Myelomonocytic Leukemia and Myelodysplastic Syndromes

• Published in: Clinical cancer research Vol. 21; no. 15; pp. 3541 - 3551
• Main Authors: Tsai, Shu-Chun, Shih, Lee-Yung, Liang, Sung-Tzu, Huang, Ying-Jung, Kuo, Ming-Chung, Huang, Chein-Fuang, Shih, Yu-Shu, Lin, Tung-Huei, Chiu, Ming-Chun, Liang, Der-Cherng
• Format: Journal Article
• Language: English
• Published: United States 01.08.2015
• Subjects: Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Core Binding Factor Alpha 2 Subunit - genetics; Core Binding Factor beta Subunit - genetics; Core Binding Factor beta Subunit - metabolism; Disease Progression; DNA Mutational Analysis; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Gene Expression Regulation, Leukemic - genetics; HEK293 Cells; Humans; Leukemia, Myelomonocytic, Chronic - genetics; Leukemia, Myelomonocytic, Chronic - pathology; Male; Mutation; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - pathology; Neoplasm Proteins - biosynthesis; Prognosis; Receptor, Macrophage Colony-Stimulating Factor - genetics
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-14-2203

Transcription factor RUNX1 is essential for normal hematopoiesis. High mutation frequencies of RUNX1 gene in chronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS) have been described, whereas the biologic significances of the mutations were not investigated. Here, we aimed to correlate the biologic activities of the RUNX1 mutants with the clinical outcomes of patients. We examined the mutational status of RUNX1 in 143 MDS and 84 CMML patients. Then, we studied the DNA and CBFβ binding abilities of all the RUNX1 mutants identified by using electrophoretic mobility shift assay and co-immunoprecipitation assay, and also determined their activities on target C-FMS gene induction by Western blotting and luciferase reporter assay. Using luciferase reporter assay, the relative biologic activities of each RUNX1 mutant could be quantified and correlated with the patient outcomes by statistical analyses. We observed that most RUNX1 mutants had reduced abilities in DNA binding, CBFβ heterodimerization, and C-FMS gene induction. The relative biologic activities of RUNX1 mutants were grouped into high- and low-activity mutations. Correlation of the activities of RUNX1 mutants with the clinical outcomes revealed that patients harboring lower activities of RUNX1 mutants had a higher risk and shorter time to secondary acute myeloid leukemia transformation in MDS and CMML. In multivariate analysis, low RUNX1 activity remained an independent predictor for secondary acute myeloid leukemia-free survival in MDS patients. The biologic activity rather than the mutational status of RUNX1 might be an indicator in predicting outcome of patients with MDS and CMML.