ABSTRACT
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.
Subject(s)
Chromosomes, Human, Pair 12 , Intracellular Signaling Peptides and Proteins/deficiency , Intracellular Signaling Peptides and Proteins/genetics , Leukemia, Prolymphocytic, T-Cell/genetics , Sequence Deletion , Animals , Ataxia Telangiectasia Mutated Proteins , Cell Cycle Proteins/genetics , Chromosome Mapping , Cyclin-Dependent Kinase Inhibitor p27 , DNA Primers , DNA-Binding Proteins/genetics , Gene Deletion , Humans , Leukemia, Prolymphocytic, T-Cell/pathology , Mice , Mice, Transgenic , Open Reading Frames , Polymerase Chain Reaction , Polymorphism, Single Nucleotide , Protein Serine-Threonine Kinases/genetics , Tumor Cells, Cultured , Tumor Suppressor Proteins/geneticsABSTRACT
Mutations in the CSA or CSB complementation genes cause the Cockayne syndrome, a severe genetic disorder that results in patients' death in early adulthood. CSA and CSB act in a transcription-coupled repair (TCR) pathway, but their functional relationship is not understood. We have previously shown that CSA is a subunit of an E3 ubiquitin ligase complex. Here we demonstrate that CSB is a substrate of this ligase: Following UV irradiation, CSB is degraded at a late stage of the repair process in a proteasome- and CSA-dependent manner. Moreover, we demonstrate the importance of CSB degradation for post-TCR recovery of transcription and for the Cockayne syndrome. Our results unravel for the first time the functional relationship between CSA and CSB.
