Cellular Expression of Antiapoptotic BCL-2 Oncoprotein in Newly Diagnosed Childhood Acute Lymphoblastic Leukemia: A Children's Cancer Group Study

Uckun, Fatih M.; Yang, Zhiwen; Sather, Harland N.; Steinherz, Peter G.; Nachman, James B.; Bostrom, Bruce; Crotty, Lisa; Sarquis, Mireille; Ek, Rauf Onur; Zeren, Tamer; Tubergen, David G.; Reaman, Gregory H.; Gaynon, Paul S.

doi:10.1182/blood.v89.10.3769

Cited by 71 publications

(21 citation statements)

References 48 publications

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“…Levels of bcl-2 expression among our precursor B-ALL cases, although higher than haematogones, were quite variable, similar to what others have reported for both paediatric and adult precursor B-ALL (Campos et al, 1996;Coustan-Smith et al, 1996;Uckun et al, 1997). As mentioned previously, levels of bcl-2 in precursor B-ALL do not appear to correlate with Bcl-2 analysis of a post-treatment B-ALL marrow specimen.…”

Section: Discussionsupporting

confidence: 87%

“…(B) However, mean bcl-2 levels are higher than those in the more mature B-cell and T-cell populations that are also present, consistent with recurrent B-ALL. clinical responses to treatments or markers of prognosis (Campos et al, 1996;Coustan-Smith et al, 1996;Uckun et al, 1997;Hogarth & Hall, 1999). The variation in levels of bcl-2 expression observed in our B-ALL cases also did not appear to correlate with any phenotypic features of our cases.…”

Section: Discussionmentioning

confidence: 44%

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Flow cytometric analysis of BCL‐2 can distinguish small numbers of acute lymphoblastic leukaemia cells from B‐cell precursors

Hartung¹,

Bahler²

2004

Br J Haematol

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SummaryFlow cytometric identification of small numbers of precursor B-cell acute lymphoblastic leukaemia (B-ALL) cells in post-treatment marrow specimens could benefit from the identification of additional, easily detectable markers that could be used in most cases. In this study, we evaluate whether bcl-2 expression quantified by four-colour flow cytometry can be effectively used to discriminate precursor B-ALL blasts from normal B-cell precursors (haematogones) and function as a leukaemia-specific marker. Levels of bcl-2 in the 22 precursor B-ALL cases studied were found to be significantly higher (over sixfold higher on average) than those present in haematogone populations from 22 control marrow specimens. Higher relative levels of bcl-2 expression in the B-ALL cases were maintained with respect to both immature CD34 + and more mature CD34 ) haematogone subsets, and appeared stable. Dilutional studies indicated that multiparameter flow cytometry analysis using bcl-2 could identify precursor B-ALL blasts representing as few as 1% of CD19 + cells or 0AE01% of total leucocytes in bone marrow specimens containing substantial numbers of haematogones. This study suggests that bcl-2 may be an important marker for flow cytometric detection and quantification of small numbers of residual precursor B-ALL cells in bone marrow specimens.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 44%

Flow cytometric analysis of BCL‐2 can distinguish small numbers of acute lymphoblastic leukaemia cells from B‐cell precursors

Hartung¹,

Bahler²

2004

Br J Haematol

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“…Targeting Apoptosis in Leukaemias with t(4;11) ª 2008 The Authors Journal Compilation ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 141, 827-839 described before (Maung et al, 1994;Coustan-Smith et al, 1996;Uckun et al, 1997). Similarly, variable and sometimes substantial BCL2 mRNA expression levels also were detected in the other leukaemia subtypes studied here; however, these results should be interpreted with caution because only a small number of cases were examined.…”

Section: Discussionmentioning

confidence: 49%

Abundant anti‐apoptotic BCL‐2 is a molecular target in leukaemias with t(4;11) translocation

Robinson¹,

Behling²,

Gupta

et al. 2008

Br J Haematol

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Summary Chemotherapy resistance from imbalanced apoptosis regulation may contribute to poor outcome in leukaemias with t(4;11). Anti‐apoptotic BCL‐2 expression and target modulation were characterized in cell lines with t(4;11) and BCL‐2 expression was examined in MLL and non‐MLL infant/paediatric leukaemia cases by Western blot analysis and/or real‐time polymerase chain reaction. Cytotoxicity of Genasense™ (Oblimersen Sodium, G3139) alone or combined with cytotoxic drugs was assessed by MTT [(3‐4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide] assays of the cell lines, applying pharmacostatistical response surface modelling of drug interactions. Apoptosis and cell cycle were evaluated by flow cytometry in RS4:11 cells. Primary leukaemias and cell lines with t(4;11) expressed abundant BCL2 mRNA and protein. Variable, sometimes substantial BCL2 mRNA was detected in other leukaemia subtypes. G3139 reduced BCL2 mRNA and protein in RS4:11 cells. The most sensitive cell line to single‐agent G3139 was RS4:11. Low G3139 concentrations sensitized RS4:11 and MV4‐11 cells to select anti‐leukaemia cytotoxic drugs. In RS4:11 cells, combining G3139 with doxorubicin (ADR) increased active caspase 3 and TUNEL staining compared to ADR alone, indicating greater apoptosis, and G3139 increased S‐phase progression. The abundant BCL‐2 affords a molecular target in leukaemias with t(4;11). G3139 exhibits preclinical activity and synergy with select cytotoxic agents in RS4:11 and MV4‐11 cells, and these effects occur through apoptosis.

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“…In a previous study, we demonstrated that in childhood acute lymphoblastic leukaemia (ALL) the interpatient levels of Bcl-2 and Bax, as well as the Bax to Bcl-2 ratio, are highly variable. Lower Bcl-2 correlated with factors commonly associated with unfavourable prognosis i.e., WBC, T-lineage, (Salomons et al, 1997;Uckun et al, 1997) chromosomal translocations and poor outcome (Coustan-Smith et al, 1996). By contrast, Bax and the Bax:Bcl-2 did not correlate with clinical features at presentation (Salomons et al, 1997), but the values of Bax:Bcl-2 found in untreated blasts spans the range of values that in in vitro models corresponded to increased sensitivity to glucocorticoid-induced apoptosis (Brady et al, 1996;Salomons et al, 1997).…”

mentioning

confidence: 85%

Mutational analysis of Bax and Bcl2 in childhood acute lymphoblastic leukaemia

Salomons¹,

Buitenhuis²,

Muñoz³

et al. 1998

Int. J. Cancer

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In childhood acute lymphoblastic leukaemia there are large interpatient variations in levels of the apoptosis-regulating proteins Bax and Bcl-2, but the molecular basis for this variation is unknown. Point-mutations in bax have been reported in cell lines derived from haematological malignancies. Frameshift mutations, which result in reduced Bax levels, have also been found in colon cancer of the microsatellite mutator phenotype. Bcl-2 overexpression, or gain of function mutations in the open reading frame (ORF) or in the translational repressor, the upstream ORF (uORF) of bcl-2, might also be important in deregulating its function or expression. We have therefore analyzed 21 bone marrow aspirates from untreated childhood acute lymphoblastic leukaemia and 2 from myeloid leukaemia for mutations in bax and bcl-2. DNA sequence analysis of the ORFs of bax and bcl-2 and of the uORF of bcl-2 revealed no mutations, despite the large range in expression levels. Thus, mutations within the (u)ORFs of bax and bcl-2 that (in)activate or deregulate Bax and Bcl-2 are infrequent in primary childhood acute leukaemia and do not play a major role in regulation of the encoded proteins in this disease.

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Cellular Expression of Antiapoptotic BCL-2 Oncoprotein in Newly Diagnosed Childhood Acute Lymphoblastic Leukemia: A Children's Cancer Group Study

Cited by 71 publications

References 48 publications

Flow cytometric analysis of BCL‐2 can distinguish small numbers of acute lymphoblastic leukaemia cells from B‐cell precursors

Flow cytometric analysis of BCL‐2 can distinguish small numbers of acute lymphoblastic leukaemia cells from B‐cell precursors

Abundant anti‐apoptotic BCL‐2 is a molecular target in leukaemias with t(4;11) translocation

Mutational analysis of Bax and Bcl2 in childhood acute lymphoblastic leukaemia

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