Haploinsufficiency of CDKN1B contributes to leukemogenesis in T-cell prolymphocytic leukemia.
T-cell prolymphocytic leukemia (T-PLL) is consistently associated with inactivation of the ATM gene and chromosomal re-arrangements leading to an overexpression of MTCP1/TCL1 oncoproteins. These alterations are present at the earliest stage of malignant transformation, suggesting that additional events are required for overt malignancy. In this study, we pursued the investigation of the 12p13 deletion, previously shown to occur in approximately half of T-PLLs. We refined the minimal region of deletion by single nucleotide and microsatellite polymorphism allelotyping. We defined a 216-kb region containing the CDKN1B gene that encodes the cyclin-dependent kinase inhibitory protein p27(KIP1). Sequencing this gene in 47 T-PLL patient samples revealed a nonsense mutation in one case without 12p13 deletion. The absence of biallelic inactivation of CDKN1B for most patients suggested a haploinsufficiency mechanism for tumor suppression, which was investigated in an animal model of the disease. In a Cdkn1b(+/-) background, MTCP1 transgenics had consistent and multiple emergences of preleukemic clones not observed in control cohorts. The second Cdkn1b allele was maintained and expressed in these preleukemic clones. Altogether, these data strongly implicate CDKN1B haploinsufficiency in the pathogenesis of T-PLL.
Le Toriellec
Emilie
E
Institut Curie, Centre de Recherche, Paris.
Despouy
Gilles
G
Pierron
Gaëlle
G
Gaye
Nogaye
N
Joiner
Marjorie
M
Bellanger
Dorine
D
Vincent-Salomon
Anne
A
Stern
Marc-Henri
MH
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics*; D015461:Leukemia, Prolymphocytic, T-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016366:Open Reading Frames; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017384:Sequence Deletion; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics
C436291:CDKN1B protein, human; D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases