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Chronic lymphocytic leukemia (CLL) major stereotyped subset 2 (IGHV3-21/IGLV3-21, ∼2.5% of all cases of CLL) is an aggressive disease variant, irrespective of the somatic hypermutation (SHM) status of the clonotypic IGHV gene. Minor stereotyped subset 169 (IGHV3-48/IGLV3-21, ∼0.2% of all cases of CLL) is related to subset 2, as it displays a highly similar variable antigen-binding site. We further explored this relationship through next-generation sequencing and crystallographic analysis of the clonotypic B-cell receptor immunoglobulin. Branching evolution of the predominant clonotype through intraclonal diversification in the context of ongoing SHM was evident in both heavy and light chain genes of both subsets. Molecular similarities between the 2 subsets were highlighted by the finding of shared SHMs within both the heavy and light chain genes in all analyzed cases at either the clonal or subclonal level. Particularly noteworthy in this respect was a ubiquitous SHM at the linker region between the variable and the constant domain of the IGLV3-21 light chains, previously reported as critical for immunoglobulin homotypic interactions underlying cell-autonomous signaling capacity. Notably, crystallographic analysis revealed that the IGLV3-21-bearing CLL subset 169 immunoglobulin retains the same geometry and contact residues for the homotypic intermolecular interaction observed in subset 2, including the SHM at the linker region, and, from a molecular standpoint, belong to a common structural mode of autologous recognition. Collectively, our findings document that stereotyped subsets 2 and 169 are very closely related, displaying shared immunoglobulin features that can be explained only in the context of shared functional selection.

BCR-ABL1-negative myeloproliferative disorders and chronic myeloid leukaemia are haematologic malignancies characterised by single and mutually exclusive genetic alterations. Nevertheless, several patients co-expressing the JAK2V617F mutation and the BCR-ABL1 transcript have been described in the literature. We report the case of a 61-year-old male who presented with an essential thrombocythaemia phenotype and had a subsequent diagnosis of chronic phase chronic myeloid leukaemia. Colony-forming assays demonstrated the coexistence of 2 different haematopoietic clones: one was positive for the JAK2V617F mutation and the other co-expressed both JAK2V617F and the BCR-ABL1 fusion gene. No colonies displayed the BCR-ABL1 transcript alone. These findings indicate that the JAK2V617F mutation was the founding genetic alteration of the disease, followed by the acquisition of the BCR-ABL1 chimeric oncogene. Our data support the hypothesis that a heterozygous JAK2V617F clone may have favoured the bi-clonal nature of this myeloproliferative disorder, generating clones harbouring a second transforming genetic event.

Multidrug resistance based on ABC transporters\' gene expression is one of the most important health challenges through chemotherapy of patients. This resistance can cause relapse or treatment failure. The goal of this conducted study was to evaluate the results of published reports which considered ABC transporters\' gene expression in pediatric patients with acute leukemia. PubMed as a free search engine was chosen. The following Mesh terms were used as: \"ATP-binding cassette transporters\" OR \"ABC-transporters*\" AND \"gene expression*\" AND \"leukemia\" OR \"ALL\" OR \"AML\" OR \"acute leukemia*\". Age was set as an additional filter with the age range of birth to 18 years old. Initial screening was performed according to inclusion and exclusion criteria and the quality of the selected papers was assessed. Papers categorized into three sections as: pediatric patients with ALL (6 papers from 1998-2015); pediatric patients with AML (3 papers from 1992-2011) and pediatric patients with ALL and AML (7 papers from 1992-2014). Totally 1118 patients enrolled in the searched studies (ALL and AML: 488; ALL: 405; AML: 225). The common method for evaluating gene expression of ABC transporters was RT-PCR. More than 50% of the papers showed the influence of ABC transporters\' gene expression on prognosis and treatment failures of patients. Despite controversial results, the gathered information in the current report serves as a comprehensive referential resource, which can be beneficial for future planning around this title, especially in developing countries.

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Methylation changes are frequent in cancers, but understanding how hyper- and hypomethylated region changes coordinate, associate with genomic features, and affect gene expression is needed to better understand their biological significance. The functional significance of hypermethylation is well studied, but that of hypomethylation remains limited. Here, with paired expression and methylation samples gathered from a patient/control cohort, we attempt to better characterize the gene expression and methylation changes that take place in cancer from B cell chronic lymphocyte leukemia (B-CLL) samples.
Across the dataset, we found that consistent differentially hypomethylated regions (C-DMRs) across samples were relatively few compared to the many poorly consistent hypo- and highly conserved hyper-DMRs. However, genes in the hypo-C-DMRs tended to be associated with functions antagonistic to those in the hyper-C-DMRs, like differentiation, cell-cycle regulation and proliferation, suggesting coordinated regulation of methylation changes. Hypo-C-DMRs in B-CLL were found enriched in key signaling pathways like B cell receptor and p53 pathways and genes/motifs essential for B lymphopoiesis. Hypo-C-DMRs tended to be proximal to genes with elevated expression in contrast to the transcription silencing-mechanism imposed by hypermethylation. Hypo-C-DMRs tended to be enriched in the regions of activating H4K4me1/2/3, H3K79me2, and H3K27ac histone modifications. In comparison, the polycomb repressive complex 2 (PRC2) signature, marked by EZH2, SUZ12, CTCF binding-sites, repressive H3K27me3 marks, and \"repressed/poised promoter\" states were associated with hyper-C-DMRs. Most hypo-C-DMRs were found in introns (36 %), 3\' untranslated regions (29 %), and intergenic regions (24 %). Many of these genic regions also overlapped with enhancers. The methylation of CpGs from 3\'UTR exons was found to have weak but positive correlation with gene expression. In contrast, methylation in the 5\'UTR was negatively correlated with expression. To better characterize the overlap between methylation and expression changes, we identified correlation modules that associate with \"apoptosis\" and \"leukocyte activation\".
Despite clinical heterogeneity in disease presentation, a number of methylation changes, both hypo and hyper, appear to be common in B-CLL. Hypomethylation appears to play an active, targeted, and complementary role in cancer progression, and it interplays with hypermethylation in a coordinated fashion in the cancer process.

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Change in ABO antigen expression on the surface of neoplastic cells have been seen for a variety of tumor types. This phenomenon has been linked with myeloid neoplasms as well but is reported infrequently. Here, we report a rare cause of ABO discrepancy in an elderly female having chronic myeloid leukemia.

BACKGROUND: To improve the outcome of patients with T-cell acute lymphoblastic leukemia (T-ALL), characterization of the biological features of T-ALL blast cells and the immune status of patients with T-ALL is needed to identify specific therapeutic strategies.
RESULTS: Using a novel approach based on the combination of fine-tiling comparative genomic hybridization (FT-CGH) and ligation-mediated PCR (LM-PCR), we molecularly identified a malignant γδ + T cell clone with a Vδ5Dδ2Jδ1 rearrangement that was paired with a T cell receptor (TCR) VγI and comprised a Vγ1Vδ5 T cell clone in a relapse T-ALL patient. This malignant Vδ5 T cell clone disappeared after chemotherapy, but the clone was detected again when disease relapsed post allogeneic hematopoietic stem cell transplantation (allo-HSCT) at 100 weeks. Using PCR and GeneScan analyses, the distribution and clonality of the TCR Vγ and Vδ subfamilies were examined before and after allo-HSCT in the patient. A reactive T cell clone with a Vδ4Dδ3Jδ1 rearrangement was identified in all samples taken at different time points (i.e., 4, 8, 68, 100 and 108 weeks after allo-HSCT). The expression of this Vδ4+ T cell clone was higher in the patient during complete remission (CR) post allo-HSCT and at disease relapse.
CONCLUSIONS: This study established a sensitive methodology to detect T cell subclones, which may be used to monitor minimal residual disease and immune reconstitution.