SIGNIFICANCE: These results demonstrate the efficacy of ABT-199 <i>in vivo</i> and provide encouraging preclinical data of Bcl-2 as a potential target for the treatment of hypodiploid B-ALL.
Early intervention strategies by rational combination of Bcl-2 blockage may constitute a promising new treatment option to GC-resistant ALL and significantly improving the chances of treating poor prednisone responders.
Other new strategies include the incorporation of tyrosine kinase inhibitor-based therapy for patients with Philadelphia chromosome-like ALL and the use of DOT inhibitors and bcl-2/bcl-xl inhibitors in R/R disease.
Results BCL2L12 expression was significantly increased in childhood ALL and correlated with higher BCL2/BAX expression ratio and favorable disease markers.
circPVT1 was highly expressed in ALL compared with normal bone marrow samples. circPVT1 expression was also significantly higher in ALL cell lines. circPVT1 knockdown inhibited cell proliferation and induced cell apoptosis through suppression of its neighbor gene c-Myc, and antiapoptotic Bcl-2 protein expression.
The studied parameters, BCL-2 protein (p less than 0.001), TOS (p less than 0.001) and LDH (p less than 0.001) were significantly elevated in the ALL group compared to the normal group (N-group).
We demonstrate that in contrast to the clear dependence of CLL on BCL-2 alone, effective antileukemic activity in the majority of ALL xenografts requires concurrent inhibition of both BCL-2 and BCL-XL We identify BCL-XL expression as a key predictor of poor response to venetoclax and demonstrate that concurrent inhibition of both BCL-2 and BCL-XL results in synergistic killing in the majority of ALL xenografts.
As the role of RBP2 in regulating apoptosis was confirmed, RBP2 overexpression and activation of BCL2 might play important roles in ALL development and progression.
In both AML and ALL groups, beclin-1 and MAB1LC3B expressions were significantly down-regulated (p < 0.001), while HIF-1α (p < 0.01) and Bcl-2 (p < 0.001) expressions were significantly up-regulated compared to the control group.
BCL2 expression and BCL2/BAX ratio were strongly upregulated in ch-ALL compared to healthy children and were correlated with favorable prognostic disease features.
Our results suggest that BCL2-938C > A genotyping may be beneficial for therapy response prediction in ALL patients, and warrant examination in a larger cohort to validate its usefulness for treatment stratification of pediatric ALL patients.
We characterized in vitro sensitivity to the pan-antiapoptotic BCL-2 family inhibitor obatoclax mesylate in diagnostic leukemia cells from 54 infants with ALL/bilineal acute leukemia because of the role of prosurvival BCL-2 proteins in resistance, their imbalanced expression in infant ALL, and evidence of obatoclax activity with a favorable toxicity profile in early adult leukemia trials.
Adult patients with acute lymphoblastic leukemia (ALL) were evaluated to determine whether presence/absence of BCR-ABL induced differences in activation of Src, PI3K/Akt and NF-κB or in the expression of anti-apoptotic proteins such as BCL-2 and c-IAP1.
High expression of MDR1 and BCL-2 in AML and MRP1 gene in ALL was associated with response to induction chemotherapy (p=0.001, p=0.02 and p=0.007 respectively).
Expression of 14 new miRNAs inversely correlated with expression of predicted target genes (-0.49 ≤ Spearman's correlation coefficients (Rs)≤ -0.27, P ≤ 0.05); among others, low levels of novel sol-miR-23 associated with high levels of its predicted (antiapoptotic) target BCL2 (B-cell lymphoma 2) in precursor B-ALL (Rs -0.36, P = 0.007).
The levels of mRNA expression of the apoptosis-related genes CASP3, CASP8, CASP9, FAS, and BCL2 were analyzed by quantitative real-time PCR in consecutive samples from 139 consecutive children with ALL at diagnosis treated by the Brazilian protocol (GBTLI-ALL 99).
ABT-737, a Bcl-2 homology domain 3 mimetic (for structure, see Nature 435:677-681, 2005) inhibits the prosurvival function of Bcl-2, Bcl-X(L), and Bcl-w. We show that ABT-737 was effective as a single agent against a panel of pediatric acute lymphoblastic leukemia (ALL) xenografts, previously established, from patient biopsies, in immunodeficient mice.
We performed systematic analyses of expression, GC regulation and function of BCL2 molecules in primary ALL lymphoblasts and a corresponding in vitro model.
The aim of this study was to characterize the involvement of Bcl-2 family members and caspase activation in dexamethasone(Dex)-induced apoptosis in ALL.