title: CALM-AF10+ T-ALL expression profiles are characterized by overexpression of HOXA and BMI1 oncogenes.
abstract: The t(10;11)(p13;q14-21) is found in T-ALL and acute myeloid leukemia and fuses CALM (Clathrin-Assembly protein-like Lymphoid-Myeloid leukaemia gene) to AF10. In order to gain insight into the transcriptional consequences of this fusion, microarray-based comparison of CALM-AF10+ vs CALM-AF10- T-ALL was performed. This analysis showed upregulation of HOXA5, HOXA9, HOXA10 and BMI1 in the CALM-AF10+ cases. Microarray results were validated by quantitative RT-PCR on an independent group of T-ALL and compared to mixed lineage leukemia-translocated acute leukemias (MLL-t AL). The overexpression of HOXA genes was associated with overexpression of its cofactor MEIS1 in CALM-AF10+ T-ALL, reaching levels of expression similar to those observed in MLL-t AL. Consequently, CALM-AF10+ T-ALL and MLL-t AL share a specific HOXA overexpression, indicating they activate common oncogenic pathways. In addition, BMI1, located close to AF10 breakpoint, was overexpressed only in CALM-AF10+ T-ALL and not in MLL-t AL. BMI1 controls cellular proliferation through suppression of the tumor suppressors encoded by the CDKN2A locus. This locus, often deleted in T-ALL, was conserved in CALM-AF10+ T-ALL. This suggests that decreased CDKN2A activity, as a result of BMI1 overexpression, contributes to leukemogenesis in CALM-AF10+ T-ALL. We propose to define a HOXA+ leukemia group composed of at least MLL-t, CALM-AF10 and HOXA-t AL, which may benefit from adapted management.
authors.affiliation: Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: W A
authors.initials: WA
authors.lastname: Dik
authors.forename: W
authors.initials: W
authors.lastname: Brahim
authors.forename: C
authors.initials: C
authors.lastname: Braun
authors.forename: V
authors.initials: V
authors.lastname: Asnafi
authors.forename: N
authors.initials: N
authors.lastname: Dastugue
authors.forename: O A
authors.initials: OA
authors.lastname: Bernard
authors.forename: J J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: A W
authors.initials: AW
authors.lastname: Langerak
authors.forename: E A
authors.initials: EA
authors.lastname: Macintyre
authors.forename: E
authors.initials: E
authors.lastname: Delabesse
mesh_terms: D000293:Adolescent; D000328:Adult; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002648:Child; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000502:physiology; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000502:physiology; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: C114359:AF10-CALM fusion protein, human; C069077:BMI1 protein, human; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C088144:HoxA protein; D063150:Polycomb Repressive Complex 1