Discovery of New Benzothiazole-Based Inhibitors of Breakpoint Cluster Region-Abelson Kinase Including the T315I Mutant

2013 ◽  
Vol 56 (9) ◽  
pp. 3531-3545 ◽  
Author(s):  
Seunghee Hong ◽  
Jinhee Kim ◽  
Sun-Mi Yun ◽  
Hyunseung Lee ◽  
Yoonsu Park ◽  
...  
Keyword(s):  
Breakpoint Cluster Region ◽  
Cluster Region ◽  
Abelson Kinase

scholarly journals FUSI GEN BREAKPOINT CLUSTER REGION ABELSON KINASE (BCRABL) DAN UJI HEMATOLOGIS RUTIN

2016 ◽  
Vol 20 (1) ◽  
pp. 47
Author(s):  
Delita Prihatni ◽  
Ida Parwati ◽  
Rahmat Sumantri ◽  
Rully MA. Roesli ◽  
Nurizzatun Nafsi
Keyword(s):  
Fusion Gene ◽  
Quantitative Polymerase Chain Reaction ◽  
Chromosomal Translocation ◽  
Chronic Phase ◽  
Myeloproliferative Disorders ◽  
Breakpoint Cluster Region ◽  
Cluster Region ◽  
Abelson Kinase ◽  
Polymerase Chain ◽  
Glucose 6 Phosphate Dehydrogenase

Chronic myeloid leukemia (CML) is a type of Chronic myeloproliferative disorders in pluripotencial stem cell haematopoiesis cell disease caused by somatic mutation chromosomal translocation of the Abelson (ABL) and Breakpoint Cluster Region (BCR) genes on chromosomes 9 and 22. The Breakpoint Cluster Region Abelson Kinase (BCR-ABL) gene encodes different fusion transcripts of messenger Ribo Nucleic acid (m RNA)/type of fusion gene that vary in size depending on the breakpoint in the BCR gene. The majority of CMLcases have been shown to have either b3a2 or b2a2 fusion gene. This research is a preliminary study designed to know how to identify a quantification BCR-ABL gene and expression fusion of gene and its relation to routine haematological parameters. The researchers analyzed 12 adults who were positive using a quantification ratio BCR-ABL and Glucose-6-Phosphate Dehydrogenase (G6PDH) as a house keeping gene by real-time quantitative polymerase chain reaction (RQ PCR) of chronic phase of CML patients, qualitative of translocation of BCR-ABL gene by gel agarose and routine haematological tests by a haematologic analyzer. The average quantification ratio of BCRABL gene and G6PDH was 0.0881, 50% patients had b3a2 fusion gene, 41.6% had b2a2 dan 0.4% had e1a1. Fusion gene b3a2 showed a quantification ratio, haemoglobin level and leukocyte count higher compared to b2a2 fusion gene.

scholarly journals Breakpoint Cluster Region–Mediated Inflammation Is Dependent on Casein Kinase II

2016 ◽  
Vol 197 (8) ◽  
pp. 3111-3119 ◽  
Author(s):  
Jie Meng ◽  
Jing-Jing Jiang ◽  
Toru Atsumi ◽  
Hidenori Bando ◽  
Yuko Okuyama ◽  
...  
Keyword(s):  
Casein Kinase Ii ◽  
Casein Kinase ◽  
Breakpoint Cluster Region ◽  
Cluster Region

scholarly journals Targeted Next Generation Sequencing Reveals a Third Breakpoint Cluster Region and New Partner Genes in the KMT2A Recombinome

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3327-3327
Author(s):  
Claus Meyer ◽  
Patrizia Larghero ◽  
Bruno Lopes ◽  
Aurélie Caye-Eude ◽  
Hélène Cavé ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Multiplex Pcr ◽  
Conflicts Of Interest ◽  
Future Research ◽  
Striking Difference ◽  
Elongation Complex ◽  
Long Distance ◽  
Acute Leukemias ◽  
Breakpoint Cluster Region ◽  
Cluster Region

Abstract Chromosomal rearrangements of the KMT2A gene are associated with acute leukemias and myelodysplastic syndromes. The large number of known KMT2A fusions (>100) renders a precise diagnosis a demanding task. More than 50% of all KMT2A partner genes have been analyzed at the DCAL, including the novel partner genes BCAS4, FAM13A, RANBP3, and STK4. Even though all KMT2A rearrangements are associated with high-risk acute leukemia, the outcome (poor or very poor) is influenced by the partner gene. So far, we have analyzed more than 3,200 patients positive for a KMT2A rearrangement. The breakpoints of these cases are located mainly in the major breakpoint cluster region (bcr1) and to a small extent in the recently described minor bcr (bcr2). A small number of breakpoints were also found outside of these two bcrs. Most of these patients were analyzed by long distance inverse (LDI)- or multiplex-PCR which only cover bcr1. More recently, we used targeted KMT2A-NGS with whole gene coverage in over 450 patients, which was initially applied selectively in patients negative by LDI- and multiplex-PCR and then used more widely. Within the KMT2A-NGS group, 410 patients had bcr1 breakpoints mainly between the KMT2A exons 7 and 13, while 46 patients bcr2 breakpoints mainly between exons 20 and 24. Of note, five patients had their breakpoint outside of these two bcrs: three of them within intron 2 and no functional KMT2A rearrangement; the other two within intron 35 and intron 36, fusing almost the whole KMT2A gene in frame to the respective partner genes ARHGEF12 and MLLT4. These two breakpoints may define a third and rare bcr (bcr3), although further cases are needed to support this hypothesis. Interestingly, 70 patients displayed a 3'-KMT2A deletion, indicating that the number of terminal deletions is higher than described previously. Two patients had a 5'-KMT2A deletion. All deletions started or ended in bcr1 and bcr2. We also observed a striking difference in the distribution of partner genes between bcr1 and bcr2. The most frequent translocation partners fused to bcr1 sites are transcription factors, while the partner genes linked to bcr2 sites generally code for cytosolic proteins. In bcr1, the 4 most frequent partner genes AFF1, MLLT3, MLLT1, and MLLT10, found in 80% of cases, all code for transcription factors that are part of the super elongation complex (SEC). These fusions therefore all lead to disruption of the hematopoietic lineage commitment. In contrast in bcr2, 3 partner genes USP2, MLLT4, and USP8 account for 85% of the cases. USP2 and USP8 are ubiquitin specific peptidases involved in cell signaling and exclusively fused to bcr2 in KMT2A. While MLLT4 is found as a partner in bcr1, bcr2 and bcr3 fusions; unlike other recurrent KMT2A partners linked to bcr1, it is not a transcription factor and it exerts oncogenic potential via dimerization like other cytosolic partners. We hypothesize that the oncogenic properties of USP2 and USP8 are dependent on dimerization like MLLT4 and that the most frequent fusions involving at different bcrs favor different oncogenic mechanisms: bcr1 transactivation and bcr2 dimerization. Further studies are needed to explain why USP2 and USP8 are exclusively associated with bcr2, and why the most frequent partner genes AFF1 and MLLT3 of the bcr1 are less frequent in bcr2. In conclusion, targeted NGS combined with bioinformatic analysis has expanded our knowledge of the KMT2A recombinome to include more fusion partners and has generated new hypotheses for future research on oncogenic mechanisms. Disclosures No relevant conflicts of interest to declare.

scholarly journals Detection of breakpoint cluster region- negative and nonclonal hematopoiesis in vitro and in vivo after transplantation of cells selected in cultures of chronic myeloid leukemia marrow

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2404-2410 ◽  
Author(s):  
AG Turhan ◽  
RK Humphries ◽  
CJ Eaves ◽  
MJ Barnett ◽  
GL Phillips ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematopoietic Cells ◽  
Breakpoint Cluster Region ◽  
Cluster Region ◽  
Differentiated Cells ◽  
The One

Abstract Philadelphia (Ph1) chromosome-positive clonogenic progenitors usually disappear within 4 to 6 weeks in long-term cultures established from the marrow of patients with chronic myeloid leukemia (CML). In contrast, coexisting chromosomally normal hematopoietic cells are relatively well maintained. Thus, even though normal cells are initially undetectable, they may become the predominant population. Recently, we have begun to explore the potential of such cultures as a strategy for preparing CML marrow for autografting, and based on cytogenetic studies of the differential kinetics of Ph1-positive and Ph1-negative clonogenic cells, have chosen a 10-day period in culture to obtain maximal numbers of selectively enriched normal stem cells. Here we present the results of molecular analyses of the cells regenerated in vivo for the initial three CML patients to be treated using this approach by comparison with the differentiated cells generated by continued maintenance of an aliquot of the autograft in vitro (using a slightly modified culture feeding procedure to enhance the production and release of cells into the nonadherent fraction after 4 weeks) for the one patient whose genotype made molecular analysis of clonality status also possible. These analyses showed that cells with a rearranged breakpoint cluster region (BCR) gene were not detectable by Southern blotting in either in vitro or in vivo populations of mature cells that might be assumed to represent the progeny of primitive cells present at the end of the initial 10 days in culture. Production of BCR- negative cells was also shown to be temporally correlated with the appearance of nonclonal hematopoietic cells both in culture and in vivo. These findings provide support for the view that prolonged maintenance of CML marrow cells in long-term culture may allow molecular characterization of both the BCR-genotype and clonality status of cells with in vivo regenerative potential.

scholarly journals Detection of chimeric BCR-ABL genes on bone marrow samples and blood smears in chronic myeloid and acute lymphoblastic leukemia by in situ hybridization

Blood ◽  
1994 ◽  
Vol 83 (7) ◽  
pp. 1922-1928 ◽  
Author(s):  
M Bentz ◽  
G Cabot ◽  
M Moos ◽  
MR Speicher ◽  
A Ganser ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Acute Lymphoblastic Leukemia ◽  
Yeast Artificial Chromosome ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
High Specificity ◽  
Breakpoint Cluster Region ◽  
Cluster Region ◽  
Blood Smears

Abstract The presence of BCR-ABL fusion genes has important diagnostic and prognostic implications in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). The CML-specific chimeric BCR-ABL gene with a break involving the major breakpoint cluster region (M-bcr) of the BCR-gene has been detected by means of fluorescence in situ hybridization (FISH). In this study, we present a FISH protocol that allows the detection of breaks in both the major and the minor breakpoint cluster region (m-bcr). Three hybridization signals of D107F9, a yeast artificial chromosome (YAC)-derived probe spanning the breakpoint regions of the BCR gene, were indicative of the translocation events. To increase the specificity further, this probe was combined with cos-abl 8, a cosmid probe flanking the breakpoint within the ABL gene for dual-color hybridization. Samples of 21 patients with CML, the ALL-derived cell line SUP-B15, and of seven patients with Philadelphia chromosome (Ph1)-positive ALL (three of them with breakpoints within m-bcr) were examined. BCR-ABL fusion was detected in all cases with high specificity (false-positive nuclei: mean, 0.1%). On cytogenetic preparations, the percentages of BCR-ABL- positive interphase cells ranged from 53% to 91%. Comparable efficiencies were achieved on blood smears. In conclusion, hybridization with D107F9 and cos-abl 8 allows unambiguous diagnosis of BCR-ABL genes and is likely to become an important tool for the monitoring of therapies in patients with CML and ALL.

scholarly journals Involvement of bcl-2 gene in Japanese follicular lymphoma

Blood ◽  
1989 ◽  
Vol 73 (3) ◽  
pp. 787-791 ◽  
Author(s):  
R Amakawa ◽  
S Fukuhara ◽  
H Ohno ◽  
S Doi ◽  
S Oguma ◽  
...  
Keyword(s):  
United States ◽  
Follicular Lymphoma ◽  
The United States ◽  
Chain Gene ◽  
Gene Rearrangements ◽  
Chromosome 18 ◽  
Breakpoint Cluster Region ◽  
Cluster Region ◽  
Molecular Features ◽  
Significant Difference

Abstract A t(14;18) (q32;q21) chromosome translocation is closely associated with the follicular lymphoma, which is prevalent in the United States, and the t(14;18) causes the juxtaposition of a bcl-2 gene on chromosome 18 with an immunoglobulin heavy-chain gene locus on chromosome 14. Genomic DNAs from 30 Japanese patients with follicular lymphoma were examined for the molecular features by Southern blot hybridization. Using probe b for the major breakpoint cluster region of a bcl-2 gene, the rearrangements were detected in eight patients. Six of the eight patients had breakpoints located within the major breakpoint region, while two had breakpoints outside this cluster region but within the region of the 7.5-kb SstI fragment containing the probe b sequence. In two patients, pFL-2 probe detected the bcl-2 gene rearrangements that occurred near or within the minor breakpoint cluster region. These ten patients had a rearranged JH-containing fragment that migrated with the rearranged bcl-2 fragment. In the other 20 patients, these two chromosome 18-specific DNA probes did not detect the bcl-2 rearrangements. Compared with studies performed in the United States, the statistical analysis indicates a significant difference in frequency of the bcl-2 gene rearrangements near or within the major breakpoint cluster region (P = 0.0027) and the minor breakpoint cluster region (P = 0.029). However, the distribution difference of these events was not significant.

The Breakpoint Cluster Region Gene on Chromosome 22q11 is Associated with Bipolar Disorder

2005 ◽  
Vol 57 (10) ◽  
pp. 1097-1102 ◽  
Author(s):  
Ryota Hashimoto ◽  
Takeya Okada ◽  
Tadafumi Kato ◽  
Asako Kosuga ◽  
Masahiko Tatsumi ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Region Gene ◽  
Breakpoint Cluster Region ◽  
Cluster Region ◽  
Chromosome 22Q11

scholarly journals Presenilin 1 Regulates NF-κB Activation via Association with Breakpoint Cluster Region and Casein Kinase II

2018 ◽  
Vol 201 (8) ◽  
pp. 2256-2263 ◽  
Author(s):  
Yuki Tanaka ◽  
Lavannya Sabharwal ◽  
Mitsutoshi Ota ◽  
Ikuma Nakagawa ◽  
Jing-Jing Jiang ◽  
...  
Keyword(s):  
Casein Kinase Ii ◽  
Casein Kinase ◽  
Presenilin 1 ◽  
Breakpoint Cluster Region ◽  
Cluster Region

scholarly journals Human MLL/KMT2A gene exhibits a second breakpoint cluster region for recurrent MLL–USP2 fusions

Leukemia ◽  
2019 ◽  
Vol 33 (9) ◽  
pp. 2306-2340 ◽  
Author(s):  
Claus Meyer ◽  
Bruno A. Lopes ◽  
Aurélie Caye-Eude ◽  
Hélène Cavé ◽  
Chloé Arfeuille ◽  
...  
Keyword(s):  
Breakpoint Cluster Region ◽  
Cluster Region
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