Two new cell lines from B‐prolymphocytic leukaemia: Characterization by morphology, immunological markers, karyotype and Ig gene rearrangement

Melo, Junia V.; Brito‐Babapulle, Vasantha; Foroni, Letizia; Robinson, D; Luzzatto, Lucio; Catovsky, Daniel

doi:10.1002/ijc.2910380413

Cited by 62 publications

(38 citation statements)

References 26 publications

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“…CLL cell lines (MEC1, JVM2, and JVM3), which were established from the peripheral blood of patients with CLL by EBV transformation (24,25), were obtained from the German Resource Centre for Biological Material and cultured in RPMI 1640 (Life Technologies, Inc.) supplemented with 10% FCS (Life Technologies), 1 mmol/L glutamine (Life Technologies), 1% penicillin/streptavidin (Life Technologies), and 25 mmol/L HEPES (Biochrom). TRAIL was obtained from R&D Systems, Inc., and the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) was obtained from Bachem and used to determine the dependency of apoptosis on caspase activity.…”

Section: Methodsmentioning

confidence: 99%

A Novel Paradigm to Trigger Apoptosis in Chronic Lymphocytic Leukemia

et al. 2009

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Evasion of apoptosis is a hallmark of chronic lymphocytic leukemia (CLL), calling for new strategies to bypass resistance. Here, we provide first evidence that small-molecule X-linked inhibitor of apoptosis (XIAP) inhibitors in combination with the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) present a novel approach to trigger apoptosis in CLL, including subgroups with resistant disease or unfavorable prognosis. XIAP, cellular IAP (cIAP) 1, and cIAP2 are expressed at high levels in primary CLL samples. Proof-of-concept studies in CLL cell lines show that subtoxic concentrations of XIAP inhibitors significantly enhance TRAIL-induced apoptosis and also sensitize for CD95-mediated apoptosis. Importantly also in primary CLL samples, XIAP inhibitor acts in concert with TRAIL to trigger apoptosis in 18 of 27 (67%) cases. This XIAP inhibitor-induced and TRAIL-induced apoptosis involves caspase-3 activation and is blocked by the caspase inhibitor zVAD.fmk. The cooperative interaction of XIAP inhibitor and TRAIL is even evident in distinct subgroups of patients with poor prognostic features (i.e., with 17p deletion, TP53 mutation, chemotherapy-refractory disease, or unmutated V H genes). Interestingly, cases with unmutated V H genes were significantly more sensitive to XIAP inhibitor-induced and TRAIL-induced apoptosis compared with V H gene-mutated samples, pointing to a role of B-cell receptor signaling in apoptosis regulation. By showing that XIAP inhibitors in combination with TRAIL present a new strategy to trigger apoptosis even in resistant forms and poor prognostic subgroups of CLL, our findings have important implications for the development of apoptosis-based therapies in CLL. [Cancer Res 2009;69(23):8977-86]

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Section: Methodsmentioning

confidence: 99%

A Novel Paradigm to Trigger Apoptosis in Chronic Lymphocytic Leukemia

et al. 2009

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“…Rec-1 and the myelomonocytic cell line U937 cells were maintained in RPMI 1640 medium supplemented with 2 mM L-glutamine and 10% fetal calf serum (FCS) and 50 g/ml gentamicin under standard conditions (humidified atmosphere, 95% air, 5% CO 2 , 37°C). The Epstein-Barr virus-negative MCL cell line JeKo (Jeon et al, 1998) and the JVM-2 cell line generated from a B-prolymphocytic leukemia (B-PLL) with t(11; 14)(q13;q32) (Melo et al, 1986) were kept under the same conditions except for supplementation with 20% FCS. Several studies have suggested that B-PLL is not a specific disease entity, but a blastic variant of a different lymphoma.…”

Section: Methodsmentioning

confidence: 99%

Cannabinoid Receptor-Mediated Apoptosis Induced byR(+)-Methanandamide and Win55,212-2 Is Associated with Ceramide Accumulation and p38 Activation in Mantle Cell Lymphoma

Gustafsson¹,

Christensson²,

Sander³

et al. 2006

Mol Pharmacol

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We have recently shown that cannabinoids induce growth inhibition and apoptosis in mantle cell lymphoma (MCL), a malignant B-cell lymphoma that expresses high levels of cannabinoid receptor types 1 and 2 (CB 1 and CB 2 ). In the current study, the role of each receptor and the signal transduction triggered by receptor ligation were investigated. Induction of apoptosis after treatment with the synthetic agonists R(ϩ)-was dependent on both cannabinoid receptors, because pretreatment with, specific antagonists to CB 1 and CB 2 , respectively, abrogated caspase-3 activity. Preincubation with the inhibitors 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) and 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole (SB202190) showed that phosphorylation of MAPK p38 was implicated in the signal transduction leading to apoptosis. Treatment with R(ϩ)-MA and Win55 was associated with accumulation of ceramide, and pharmacological inhibition of ceramide synthesis de novo prevented both p38 activation and mitochondria depolarization assessed by binding of 3,3Ј-dihexyloxacarbocyanine iodide (DiOC 6 ). In contrast, the pancaspase inhibitor z-Val-Ala-Asp(Ome)-CH 2 F (z-VAD-FMK) did not protect the mitochondrial integrity. Taken together, these results suggest that concurrent ligation of CB 1 and CB 2 with either R(ϩ)-MA or Win55 induces apoptosis via a sequence of events in MCL cells: accumulation of ceramide, phosphorylation of p38, depolarization of the mitochondrial membrane, and caspase activation. Although induction of apoptosis was observed in both MCL cell lines and primary MCL, normal B cells remained unaffected. The present data suggest that targeting CB 1 / CB 2 may have therapeutic potential for the treatment of mantle cell lymphoma.

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“…To this end, we knocked down the expression of PPP1CB using a lentivirus-based shRNA approach and evaluated its effects on cell proliferation in B-lymphocytic leukemia cell lines MEC1 (22) and JVM3 (24), as well as in National Institutes of Health (NIH) 3T3 and Ba/F3 cell lines. Water-soluble tetrazolium-1 (WST-1) cell proliferation assays demonstrated that in comparison with control (P < 0.01), knockdown of PPP1CB resulted in increased cell proliferation in NIH 3T3 and Ba/F3 cells (Fig.…”

Section: Validation Of Ypel5/ppp1cb and Reciprocal Fusion In Independentmentioning

confidence: 99%

Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia

Velusamy

Palanisamy

Kalyana-Sundaram

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in the Western hemisphere. Tumor-specific chromosomal translocations, characteristic findings in several human malignancies that directly lead to malignant transformation, have not been identified in CLL. Using paired-end transcriptome sequencing, we identified recurrent and reciprocal RNA chimeras involving yippee like 5 (YPEL5) and serine/threonine-protein phosphatase PP1-beta-catalytic subunit (PPP1CB) in CLL. Two of seven index cases (28%) harbored the reciprocal RNA chimeras in our initial screening. Using quantitative real-time PCR (q real-time PCR), YPEL5/PPP1CB and PPP1CB/YPEL5 fusion transcripts were detected in 97 of 103 CLL samples (95%) but not in paired normal samples, benign lymphocytes, or various unrelated cancers. Whole-genome sequencing and Southern blotting demonstrated no evidence for a genomic fusion between YPEL5 and PPP1CB. YPEL5/PPP1CB chimera, when introduced into mammalian cells, expressed a truncated PPP1CB protein that demonstrated diminished phosphatase activity. PPP1CB silencing resulted in enhanced proliferation and colony formation of MEC1 and JVM3 cells, implying a role in the pathogenesis of mature B-cell leukemia. These studies uncover a potential role for recurrent RNA chimeras involving phosphatases in the pathogenesis of a common form of leukemia. chimera splicing | next-generation sequencing | serine/threonine phosphatase PP1-beta catalytic subunit | B-lymphoid malignancy B -cell chronic lymphocytic leukemia (B-CLL) is the most common form of leukemia in adults in Western countries (1). The most common recurrent cytogenetic abnormality in CLL is a deletion involving the 13q14.3 locus, which occurs in 50% of cases and targets miR-16-1, miR-15a, and DLEU2 (2-4). Twenty percent of CLLs exhibit trisomy 12 (5). Other recurrent abnormalities in CLL include del 11q22-23 (ATM) and 17p13 (targeting p53) (6, 7). Of clinical relevance, IgV mutational status and zeta-chain associated protein kinase-70 kD (ZAP-70) expression have been associated with distinct prognostic categories of B-CLL (8-10). Recently, mutations in NOTCH1 (12.2%), MYD88 (2.9%), and XPO1 (2.4%) have been identified using next-generation sequencing (11, 12). The NOTCH1 mutations occur more frequently in cases with unmutated variable regions of the Ig heavy chain genes, whereas the MYD88 mutations occur more frequently in mutated cases (11).Although the role of genomic events is well established in the pathogenesis of cancers, the contribution of posttranscriptional RNA processing, which plays a fundamental role in control of protein expression, is less well understood.Alternative splicing can affect the translation, localization, or degradation of mRNA (13) and frequently results in the production of multiple and functionally distinct protein isoforms (14). Importantly, alternative splicing and expression of abnormal splicing chimeras may contribute to cancer pathogenesis and are associated with prognostic significance (15, 16). For exam...

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Two new cell lines from B‐prolymphocytic leukaemia: Characterization by morphology, immunological markers, karyotype and Ig gene rearrangement

Cited by 62 publications

References 26 publications

A Novel Paradigm to Trigger Apoptosis in Chronic Lymphocytic Leukemia

A Novel Paradigm to Trigger Apoptosis in Chronic Lymphocytic Leukemia

Cannabinoid Receptor-Mediated Apoptosis Induced byR(+)-Methanandamide and Win55,212-2 Is Associated with Ceramide Accumulation and p38 Activation in Mantle Cell Lymphoma

Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia

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