CALM-AF10+ T-ALL expression profiles are characterized by overexpression of HOXA and BMI1 oncogenes.
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.
Dik
W A
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Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
Brahim
W
W
Braun
C
C
Asnafi
V
V
Dastugue
N
N
Bernard
O A
OA
van Dongen
J J M
JJ
Langerak
A W
AW
Macintyre
E A
EA
Delabesse
E
E
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
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