CALM/AF10-positive leukemias show upregulation of genes involved in chromatin assembly and DNA repair processes and of genes adjacent to the breakpoint at 10p12

• Published in: Leukemia Vol. 26; no. 5; pp. 1012 - 1019
• Main Authors: Mulaw, M A, Krause, A J, Deshpande, A J, Krause, L F, Rouhi, A, La Starza, R, Borkhardt, A, Buske, C, Mecucci, C, Ludwig, W-D, Lottaz, C, Bohlander, S K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2012; Nature Publishing Group
• Subjects: Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Acute myeloid leukemia; Analysis; Angiogenesis; Animals; Antigens; Assembly; B-cell lymphoma; Biological and medical sciences; Bone marrow; Cancer Research; Care and treatment; Cell interactions; Chromatin Assembly and Disassembly - genetics; Chromatin remodeling; Chromosome Fragile Sites; Chromosome translocations; Chromosomes, Human, Pair 10; Critical Care Medicine; Deoxyribonucleic acid; DNA; DNA methylation; DNA repair; DNA Repair - genetics; Fusion protein; Gene expression; Gene regulation; Genes; Genetic aspects; Genomics; Health aspects; Heat shock proteins; Hematologic and hematopoietic diseases; Hematology; Homology; Hsp40 protein; Humans; Intensive; Internal Medicine; Leukemia; Leukemia - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphatic leukemia; Lymphoma; Medical sciences; Medicine; Medicine & Public Health; Mice; Monomeric Clathrin Assembly Proteins - genetics; Oncology; original-article; Physiological aspects; Proteins; Repair; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; RNA-directed DNA polymerase; Transcription Factors - genetics; Translocation; Translocation, Genetic; Transplantation; Transplants & implants; Up-Regulation; Germany; GSEA; microarray; myeloid and lymphoid neoplasia; genomic instability and DNA repair; CALM/AF10; Genetic mapping; Breakpoint; Chromatin; Hematology; Leukemia; Malignant hemopathy; Malignant tumor; Chromosome C10; DNA repair; Repair gene; Chromosome DNA; Genetics; Instability; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2011.307

The t(10;11)(p12;q14) is a recurring chromosomal translocation that gives rise to the CALM/AF10 fusion gene, which is found in acute myeloid leukemia, acute lymphoblastic leukemia and malignant lymphoma. We analyzed the fusion transcripts in 20 new cases of CALM/AF10 -positive leukemias, and compared the gene expression profile of 10 of these to 125 patients with other types of leukemia and 10 normal bone marrow samples. Based on gene set enrichment analyses, the CALM/AF10 -positive samples showed significant upregulation of genes involved in chromatin assembly and maintenance and DNA repair process, and downregulation of angiogenesis and cell communication genes. Interestingly, we observed a striking upregulation of four genes located immediately centromeric to the break point of the t(10;11)(p12;q14) on 10p12 ( COMMD3 (COMM domain containing 3), BMI1 (B lymphoma Mo-MLV insertion region 1 homolog), DNAJC1 (DnaJ (Hsp40) homolog subfamily C member 1) and SPAG6 (sperm associated antigen 6)). We also conducted semiquantitative reverse transcriptase-PCR analysis on leukemic blasts from a murine CALM/AF10 transplantation model that does not have the translocation. Commd3 , Bmi1 and Dnajc1 , but not Spag6 were upregulated in these samples. These results strongly indicate that the differential regulation of these three genes is not due to the break point effect but as a consequence of the CALM/AF10 fusion gene expression, though the mechanism of regulation is not well understood.