Recurrent loss, but lack of mutations, of the SMARCB1 tumor suppressor gene in T-cell prolymphocytic leukemia with TCL1A-TCRAD juxtaposition.
In T-cell prolymphocytic leukemia (T-PLL), chromosomal imbalances affecting the long arm of chromosome 22 are regarded as typical chromosomal aberrations secondary to a TCRAD-TCL1A fusion due to inv(14) or t(14;14). We analyzed recently obtained data from conventional karyotyping, SNP-chip array copy number mapping, genome-wide expression profiling, and interphase fluorescence in situ hybridization (FISH) of inv(14)-positive T-PLL with respect to structural aberrations on chromosome 22. Combined gene chip and interphase FISH analyses revealed interstitial deletions on 22q in 4 of 12 cases, with one case additionally showing a terminal copy number gain. A minimally deleted region of approximately 9.1 Mb was delineated, from 16.2 Mb (22cen) to 25.3 Mb (22q12.1). The distal borders of copy number alterations spread over a region of approximately 8.8 Mb, from 25.2 Mb (22q12.1) to 34 Mb (22q12.3). Mutation screening of candidate tumor suppressor genes SMARCB1 and CHEK2 mapping to the minimally deleted and the breakpoint regions, respectively, in cases with hemizygous deletion, revealed no inactivating mutations. With gene expression profiling, no significantly downregulated genes were identified in the minimally deleted region. We therefore assume that haploinsufficiency or alternative pathomechanisms underlie chromosome 22 aberrations in T-PLL.
Bug
Stefanie
S
Institute of Human Genetics, Christian-Albrechts University Kiel and University Hospital Schleswig-Holstein, Kiel, Germany. sbug@medgen.uni-kiel.de
Dürig
Jan
J
Oyen
Florian
F
Klein-Hitpass
Ludger
L
Martin-Subero
Jose I
JI
Harder
Lana
L
Baudis
Michael
M
Arnold
Norbert
N
Kordes
Uwe
U
Dührsen
Ulrich
U
Schneppenheim
Reinhard
R
Siebert
Reiner
R
D064447:Checkpoint Kinase 2; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D017353:Gene Deletion; D005787:Gene Frequency; D016147:Genes, Tumor Suppressor / Q000502:physiology; D005820:Genetic Testing; D006801:Humans; D015461:Leukemia, Prolymphocytic, T-Cell / Q000235:genetics*; D009154:Mutation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000071796:SMARCB1 Protein; D014157:Transcription Factors / Q000235:genetics*
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; C090851:TCL1A protein, human; D014157:Transcription Factors; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases