To identify genomic alterations in chronic lymphocytic leukemia (CLL), we performed single-nucleotide polymorphismarray analysis using Affymetrix Version 6.0 on 353 samples from untreated patients entered in the CLL8 treatment trial. Based on paired-sample analysis (n ؍ 144), a mean of 1.8 copy number alterations per patient were identified; approximately 60% of patients carried no copy number alterations other than those detected by fluorescence in situ hybridization analysis. Copy-neutral loss-ofheterozygosity was detected in 6% of CLL patients and was found most frequently on 13q, 17p, and 11q. Minimally deleted regions were refined on 13q14 (deleted in 61% of patients) to the DLEU1 and DLEU2 genes, on 11q22.3 (27% of patients) to ATM, on 2p16.1-2p15 (gained in 7% of patients) to a 1.9-Mb fragment containing 9 genes, and on 8q24.
Inhibitor of apoptosis (IAP) proteins are highly expressed in chronic lymphocytic leukemia (CLL) cells and contribute to evasion of cell death and poor therapeutic response. Here, we report that Smac mimetic BV6 dose-dependently induces cell death in 28 of 51 (54%) investigated CLL samples, while B-cells from healthy donors are largely unaffected. Importantly, BV6 is significantly more effective in prognostic unfavorable cases with, e.g., non-mutated VH status and TP53 mutation than samples with unknown or favorable prognosis. The majority of cases with 17p deletion (10/12) and Fludarabine refractory cases respond to BV6, indicating that BV6 acts independently of p53. BV6 also triggers cell death under survival conditions mimicking the microenvironment, e.g., by adding CD40 ligand or conditioned medium. Gene expression profiling identifies cell death, NF-jB and redox signaling among the top pathways regulated by BV6 not only in CLL but also in core-binding factor (CBF) acute myeloid leukemia (AML). Consistently, BV6 stimulates production of reactive oxygen species (ROS), which are contributing to BV6-induced cell death, since antioxidants reduce cell death. While BV6 causes degradation of cellular inhibitor of apoptosis (cIAP)1 and cIAP2 and nuclear factor-kappaB (NF-jB) pathway activation in primary CLL samples, BV6 induces cell death independently of caspase activity, receptor-interacting protein (RIP)1 activity or tumor necrosis factor (TNF)a, as zVAD.fmk, necrostatin-1 or TNFa-blocking antibody Enbrel fail to inhibit cell death. Together, these novel insights into BV6-regulated cell death in CLL have important implications for developing new therapeutic strategies to overcome cell death resistance especially in poor prognostic CLL subgroups.Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the Western world. 1 Key prognostic factors besides the Rai and Binet stage are chromosomal aberrations like 17p or 11q deletion, TP53 mutation and immunoglobulin heavy-chain variable region gene (IGVH) mutation status. Although individualized therapeutic strategies have been developed, the disease is still incurable. Especially patients with 17p deletion and TP53 mutation have a very poor prognosis. 2 Therefore, new therapeutic targets that act independently of functional p53 in CLL are needed.CLL is characterized by the accumulation of Blymphocytes which has been largely attributed to defective cell death pathways rather than to aberrant proliferation. [3][4][5] Apoptosis represents one of the key forms of programmed cell death. 6 Necroptosis is a caspase-independent mode of programmed cell death that typically occurs when essential factors of apoptosis such as caspases are inhibited and is regulated by RIP1 and RIP3. 7 Inhibitor of apoptosis (IAP) proteins are major regulators of cell death and survival processes. X-linked inhibitor of apoptosis (XIAP) acts as direct caspase inhibitor, 8 while cIAP1 and -2 were shown to protect cells from cell death by acting primarily as E3 ubiquitin liga...
Heterozygous microdeletions of chromosome 2p21 encompassing only the SIX2 gene have been described in two families to date. The clinical phenotype comprised autosomal-dominant inherited frontonasal dysplasia with ptosis in one family. In the second family, conductive hearing loss was the major clinical feature described; however, the affected persons also had ptosis. Here, we present a large family combining all three predescribed features of SIX2 gene deletion. The phenotype in four affected family members in three generations consisted of bilateral congenital ptosis, epicanthus inversus, frontonasal dysplasia with broad nasal bridge and hypertelorism, frontal bossing and large anterior fontanel in childhood, narrow ear canals, and mild conductive hearing loss with onset in childhood. Thus, the phenotypic spectrum of SIX2 haploinsufficiency is widened. Moreover, 2p21 microdeletions with SIX2 haploinsufficiency appear to lead to a recognizable phenotype with facial features resembling blepharophimosis-ptosis-epicanthus inversus syndrome.
Background Rare syndromic skin disorders may represent a diagnostic challenge. Aims We report a unique case associating cutaneous manifestations and developmental delay. Materials & Methods The affected 14 months old boy had poikiloderma, facial dysmorphism with deep‐set eyes, atrichia, as well as nail dysplasia and non‐descended testes. In addition, his psychomotor development was delayed. Exome sequencing and molecular karyotyping via array‐CGH (oligo‐array, 180k Agilent, design 22060) were performed. Results Mutations in RECQL4 (found in patients with RTS2) were first excluded. In the ANAPC1 gene, a novel combination of a recurrent intronic mutation (c.2705‐198C>T) and a deletion of the second ANAPC1 allele was detected, thus confirming the clinical diagnosis of RTS1. The deletion on chromosome 2q13 comprised further genes and spanned 1,7 megabases. Heterozygous deletions in this region are known as 2q13 microdeletion syndrome and are associated with developmental delay, autism and facial dysmorphism. Discussion The genetic findings most probably explain both, the RTS1 features and the developmental delay. Genetic diagnosis in RTS is indispensable to confirm the specific subtype and its associated risks: juvenile cataracts are features of RTS1 (ANAPC1 gene), whereas a high risk of osteosarcoma is part of RTS2 (RECQL4 gene). Thus, the patient described here is at high risk for the development of juvenile cataracts and requires regular ophthalmologic examination. Conclusion This case report underlines the necessity of thorough clinical diagnosis prior to genetic diagnosis of RTS1, since the recurrent intronic ANAPC1 mutation is otherwise missed.
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab can induce longterm remissions in patients with chronic lymphocytic leukemia. Treatment efficacy with Bruton's tyrosine kinase inhibitors was found similar to fludarabine, cyclophosphamide and rituximab in untreated chronic lymphocytic leukemia patients with a mutated immunoglobulin heavy chain variable gene. To identify patients who specifically benefit from fludarabine, cyclophosphamide and rituximab, we developed integrative models including established prognostic parameters and gene expression profiling. Gene expression profiling was conducted on n=337 CLL8 trial samples, “core” probe sets were summarized on gene levels and RMA normalized. Prognostic models were built using penalized Cox proportional hazards models with the smoothly clipped absolute deviation penalty. We identified a prognostic signature of less than a dozen genes, which substituted for established prognostic factors, including TP53 and immunoglobulin heavy chain variable gene mutation status. Independent prognostic impact was confirmed for treatment, β2-microglobulin and del(17p) regarding overall survival and for treatment, del(11q), del(17p) and SF3B1 mutation for progression-free survival. The combination of independent prognostic and gene expression profiling variables performed equal to models including only established non-gene expression profiling variables. Gene expression profiling variables showed higher prognostic accuracy for patients with long progression-free survival compared to categorical variables like the immunoglobulin heavy chain variable gene mutation status and reliably predicted overall survival in CLL8 and an independent cohort. Gene expression profiling based prognostic models can help to identify patients who specifically benefit from fludarabine, cyclophosphamide and rituximab treatment. The CLL8 trial is registered under EUDRACT- 2004-004938-14 and ClinicalTrials.gov Identifier NCT00281918.
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