Haploinsufficiency of CDKN1B contributes to leukemogenesis in T-cell prolymphocytic leukemia

Abstract

T-cell prolymphocytic leukemia (T-PLL) isconsistently associated with inactivation of the ATM gene and chromosomal rearrangements 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 ϩ/Ϫ 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. IntroductionT-cell prolymphocytic leukemia (T-PLL) is a rare hematologic disease of elderly people characterized by a mature T-cell phenotype, a large tumoral mass, and an aggressive clinical course. Two genetic alterations are known to play a major role in this disease. First, ATM is somatically deleted or mutated in almost 95% of T-PLL patients (for review, see Stankovic et al 1 ), and germinal mutations of ATM responsible for the ataxia telangiectasia (AT) predispose to T-PLL (for review, see Taylor et al 2 ). Second, chromosomal translocations and inversions involving TCR genes and MTCP1/TCL1 gene family members are consistently and specifically associated with T-PLL, leading to overexpression of these oncogenes. 3,4 The oncogenic role of the MTCP1/TCL1 genes was demonstrated using transgenic mouse models. 5,6 Recently, we showed that MTCP1/TCL1 oncogene expression modified T-cell homeostasis, 7 which may be related to the impairment of activationinduced cell death (AICD) by these oncoproteins. 8 ATM inactivation and MTCP1/TCL1 overexpression are present at the earliest stage of the malignant transformation in clonal T-cell populations frequently found in AT patients. However, the indolent course of these populations suggests that these events are insufficient to induce a leukemic phenotype. 9 In the search for additional events crucial for full-blown transformation, we undertook a comparative genomic hybridization analysis in a series of T-PLL cases that revealed numerous recurrent copy number alterations. 10 One of these alterations was the deletion of the 12p13 region, which was further characterized by allelotyping. This deletion was shown to occur in almost half of T-PLL cases and the minimal region of delet...

Molecular allelokaryotyping of T-cell prolymphocytic leukemia cells with high density single nucleotide polymorphism arrays identifies novel common genomic lesions and acquired uniparental disomy

“…These studies have described several differentially regulated genes possibly due to gene dosage effects 18 and CDKN1B haploinsufficiency as a new pathogenic mechanism in T-PLL. 19 Recently, SNP arrays with a higher resolution (250,000 SNPs interrogated per array) have been developed for whole genome mapping. 20 The analysis of genomic DNA with SNP arrays provides two different types of information.…”

Proteolytically cleaved MLL subunits are susceptible to distinct degradation pathways

“…These CDKIs have also been implicated in lymphoid growth control and tumorigenesis. Lymphoid cells from Cdkn2c knockout mice are hyper-proliferative to mitogens (Franklin et al, 1998), and inactivating mutations of Cdkn1b have been reported in T-ALL and other types of leukemia (Le Toriellec et al, 2008;Markaki et al, 2006). The Notch1 pathway, which is activated frequently in T-ALL, effectively reduces CDKN1B levels through upregulation of SKP2 expression (Dohda et al, 2007).…”

How I treat prolymphocytic leukemia

“…The use of high-density genomic mapping and whole-genome sequencing is likely to identify further candidate genes, leading to a better understanding of pathogenesis in T-PLL and a more directed approach to therapy. [44][45][46] How I manage B-PLL B-PLL is a very rare mature B-cell malignancy with an aggressive clinical course, refractoriness to chemotherapy, and a median survival of 3 years. In the early 1970s, B-PLL was initially described as a variant form of B-cell CLL.…”