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Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.
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Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.

Haematologica. 2018 Feb 15;:

Authors: Sinclair PB, Blair HH, Ryan SL, Buechler L, Cheng J, Clayton J, Hanna R, Hollern S, Hawking Z, Bashton M, Schwab CJ, Jones L, Russell LJ, Marr H, Carey P, Halsey C, Heidenreich O, Moorman AV, Harrison CJ

Abstract
Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of childhood precursor B-cell acute lymphoblastic leukemia. There are no cell lines with iAMP21 and these abnormalities are too complex to faithfully engineer in animal models. As a resource for future functional and pre-clinical studies, we have created xenografts from intrachromosomal amplification of chromosome 21 leukemia patient blasts and characterised them by in-vivo and ex-vivo luminescent imaging, FLOW immunophenotyping, and histological and ultrastructural analysis of bone marrow and the central nervous system. Investigation of up to three generations of xenografts revealed phenotypic evolution, branching genomic architecture and, compared with other B-cell acute lymphoblastic leukemia genetic subtypes, greater clonal diversity of leukemia initiating cells. In support of intrachromosomal amplification of chromosome 21 as a primary genetic abnormality, it was always retained through generations of xenografts, although we also observed the first example of structural evolution of this rearrangement. Clonal segregation in xenografts revealed convergent evolution of different secondary genomic abnormalities implicating several known tumour suppressor genes and a region, containing the B-cell adaptor, PIK3AP1, and nuclear receptor co-repressor, LCOR, in the progression of B-ALL. Tracking of mutations in patients and derived xenografts provided evidence for co-operation between abnormalities activating the RAS pathway in B-ALL and for their aggressive clonal expansion in the xeno-environment. Bi-allelic loss of the CDKN2A/B locus was recurrently maintained or emergent in xenografts and also strongly selected as RNA sequencing demonstrated a complete absence of reads for genes associated with the deletions.

PMID: 29449437 [PubMed - as supplied by publisher]




Mixed-species RNAseq analysis of human lymphoma cells adhering to mouse stromal cells identifies a core gene set that is also differentially expressed in the lymph node microenvironment of mantle cell lymphoma and chronic lymphocytic leukemia patients.
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Mixed-species RNAseq analysis of human lymphoma cells adhering to mouse stromal cells identifies a core gene set that is also differentially expressed in the lymph node microenvironment of mantle cell lymphoma and chronic lymphocytic leukemia patients.

Haematologica. 2018 Feb 15;:

Authors: Arvidsson G, Henriksson J, Sander B, Wright AP

Abstract
A subset of hematological cancer patients is refractory to treatment or suffers relapse, due in part to minimal residual disease, whereby some cancer cells survive treatment. Cell-adhesion mediated drug resistance is an important mechanism, whereby cancer cells receive survival signals via interaction with e.g. stromal cells. No genome-wide studies of in vitro systems have yet been performed to compare gene expression in different cell subsets within a co-culture and cells grown separately. Using RNA sequencing and species-specific read mapping, we compared transcript levels in human Jeko-1 mantle cell lymphoma cells stably adhered to mouse MS-5 stromal cells or in suspension within a co-culture or cultured separately as well as in stromal cells in co-culture or in separate culture. From 1050 differentially expressed transcripts in adherent mantle cell lymphoma cells we identified 24 functional categories that together represent four main functional themes, anti-apoptosis, B-cell signaling, cell adhesion/migration and early mitosis. A comparison with previous mantle cell lymphoma and chronic lymphocytic leukemia studies, of gene expression differences between lymph node and blood, identified 116 genes that are differentially expressed in all three studies. From these genes we suggest a core set of genes (CCL3, CCL4, DUSP4, ETV5, ICAM1, IL15RA, IL21R, IL4I1, MFSD2A, NFKB1, NFKBIE, SEMA7A, TMEM2) characteristic of cells undergoing cell-adhesion mediated microenvironment signaling in mantle cell lymphoma/chronic lymphocytic leukemia. The model system developed and characterized here together with the core gene set will be useful for future studies of pathways that mediate increased cancer cell survival and drug resistance mechanisms.

PMID: 29449436 [PubMed - as supplied by publisher]




Novel hereditary spherocytosis-associated splice site mutation in the ANK1 gene caused by parental gonosomal mosaicism.
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Novel hereditary spherocytosis-associated splice site mutation in the ANK1 gene caused by parental gonosomal mosaicism.

Haematologica. 2018 Feb 15;:

Authors: Wang X, Shen N, Huang M, Lu Y, Hu Q

PMID: 29449435 [PubMed - as supplied by publisher]




MSH6 haploinsufficiency at relapse contributes to the development of thiopurine resistance in pediatric B-lymphoblastic leukemia.
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MSH6 haploinsufficiency at relapse contributes to the development of thiopurine resistance in pediatric B-lymphoblastic leukemia.

Haematologica. 2018 Feb 15;:

Authors: Evensen NA, Madhusoodhan PP, Meyer J, Saliba J, Chowdhury A, Araten DJ, Nersting J, Bhatla T, Vincent TL, Teachey D, Hunger SP, Yang J, Schmiegelow K, Carroll WL

Abstract
Survival of children with relapsed acute lymphoblastic leukemia is poor and understanding mechanisms underlying resistance is essential in developing new therapy. Relapse-specific heterozygous deletions in MSH6, a crucial part of DNA Mismatch Repair, are frequently detected. Our aim was to determine whether MSH6 deletion results in a hypermutator phenotype associated with generation of secondary mutations involved in drug resistance or leads to a failure to initiate apoptosis directly in response to chemotherapeutic agents. We knocked down MSH6 in mismatch repair proficient cell lines (697 and UOCB1) and showed significant increases in IC50s to 6-Thioguanine & 6-Mercaptopurine (697: 26- and 9-fold; UOCB1: 5- and 8-fold) in vitro, as well as increased resistance to 6-Mercaptopurine treatment in vivo. No shift in IC50 was observed in deficient cells (Reh & RS4;11). 697 MSH6 knockdown resulted in increased DNA thioguanine nucleotide levels compared to non-targeted cells (3,070 versus 1,722 fmol/mg DNA) with no difference observed in mismatch repair deficient cells. Loss of MSH6 did not give rise to microsatellite instability in cells lines or clinical samples nor did it significantly increase mutation rate, but rather resulted in a defect in cell cycle arrest upon thiopurine exposure. MSH6 knockdown cells showed minimal activation of checkpoint regulator CHK1, ɣH2AX (DNA damage marker) and p53 levels upon treatment with thiopurines, consistent with intrinsic chemoresistance due to failure to recognize thioguanine nucleotide mismatching and initiate mismatch repair. Aberrant MSH6 adds to the list of alterations/mutations associated with acquired resistance to purine analogues emphasizing the importance of thiopurine therapy.

PMID: 29449434 [PubMed - as supplied by publisher]




Highly similar genomic landscapes in monoclonal B-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations.
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Highly similar genomic landscapes in monoclonal B-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations.

Haematologica. 2018 Feb 15;:

Authors: Agathangelidis A, Ljungström V, Scarfò L, Fazi C, Gounari M, Pandzic T, Sutton LA, Stamatopoulos K, Tonon G, Rosenquist R, Ghia P

Abstract
Despite the recent discovery of recurrent driver mutations in chronic lymphocytic leukemia, the genetic factors involved in disease onset remain largely unknown. To address this issue, we performed whole-genome sequencing in 11 individuals with monoclonal B-cell lymphocytosis, both of the low-count and high-count subtypes, and 5 patients with ultra-stable chronic lymphocytic leukemia (>10 years without progression from initial diagnosis). All three entities were indistiguishable at the genomic level exhibiting low genomic complexity and similar types of somatic mutations. Exonic mutations were infrequently identified in putative chronic lymphocytic leukemia driver genes in all settings including low-count monoclonal B-cell lymphocytosis. To corroborate these findings we also performed deep-sequencing in 11 known frequently mutated genes in an extended cohort of 28 monoclonal B-cell lymphocytosis/chronic lymphocytic leukemia cases. Interestingly, shared mutations were detected between clonal B cells and paired polymorphonuclear cells, strengthening the notion that at least a fraction of somatic mutations may occur before disease onset, likely at the hematopoietic stem-cell level. Finally, we identified previously unreported non-coding variants targeting pathways relevant to B-cell and chronic lymphocytic leukemia development, likely associated with the acquisition of the characteristic neoplastic phenotype typical of both monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.

PMID: 29449433 [PubMed - as supplied by publisher]