Figure S1-7 and Suppl. Tables from Bcl-2 Is a Therapeutic Target for Hypodiploid B-Lineage Acute Lymphoblastic Leukemia

Diaz-Flores, Ernesto; Comeaux, Evan Q.; Kim, Kailyn L.; Melnik, Ella; Beckman, Kyle; Davis, Kara L.; Wu, Kevin; Akutagawa, Jon; Bridges, Olga; Marino, Roberta; Wohlfeil, Margo; Braun, Benjamin S.; Mullighan, Charles G.; Loh, Mignon L.

doi:10.1158/0008-5472.22423031.v1

Figure S1-7 and Suppl. Tables from Bcl-2 Is a Therapeutic Target for Hypodiploid B-Lineage Acute Lymphoblastic Leukemia

https://doi.org/10.1158/0008-5472.22423031

journal contribution

posted on 2023-03-31, 03:01 authored by Ernesto Diaz-Flores, Evan Q. Comeaux, Kailyn L. Kim, Ella Melnik, Kyle Beckman, Kara L. Davis, Kevin Wu, Jon Akutagawa, Olga Bridges, Roberta Marino, Margo Wohlfeil, Benjamin S. Braun, Charles G. Mullighan, Mignon L. Loh

<p>Supplemental Figure 1. Protein and gene expression profiling of hypodiploid ALL. Supplemental Figure 2. Pairing biochemical characterization with viability/survival assays in hypodiploid B-ALL. Supplemental Figure 3. Primagraft samples used for ex vivo and in vivo experiments. Supplemental Figure 4. In vivo engraftment of hypodiploid ALL xenografts and response to ABT-199 during trial. Supplemental Figure 5. Clonal characterization of hypodiploid tumors at the beginning and end of trial. Supplemental Figure 6. Genome editing assays. Supplemental Figure 7. Genomic, karyotypic characterization and mechanistic experiments on Beck-1732 cells. Supplementary Tables of samples used in the in vivo studies.</p>

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American Cancer Society

NIH

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DOI - Is supplement to Bcl-2 Is a Therapeutic Target for Hypodiploid B-Lineage Acute Lymphoblastic Leukemia

ARTICLE ABSTRACT

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The highest rates of treatment failure occur in specific genetic subsets of ALL, including hypodiploid B-cell ALL (B-ALL), for which effective alternative therapies to current intensive chemotherapy treatments have yet to be developed. Here, we integrated biochemical and genomic profiling with functional drug assays to select effective agents with therapeutic potential against hypodiploid B-ALL. ABT-199, a selective Bcl-2 inhibitor, was effective in reducing leukemic burden in vitro and in vivo in patient-derived xenograft models of hypodiploid B-ALL. Daily oral treatment with ABT-199 significantly increased survival in xenografted mice. The unexpected efficacy of ABT-199 observed in hypodiploid leukemias lacking BIM expression (the major reported mediator of ABT-199–induced apoptosis) led us to investigate the mechanism of action of ABT-199 in the absence of BIM. Treatment with ABT-199 elicited responses in a dose-dependent manner, from cell-cycle arrest at low nanomolar concentrations to cell death at concentrations above 100 nmol/L. Collectively, these results demonstrate the efficacy of Bcl-2 inhibition and potential therapeutic strategy in hypodiploid B-ALL. These results demonstrate the efficacy of ABT-199 in vivo and provide encouraging preclinical data of Bcl-2 as a potential target for the treatment of hypodiploid B-ALL.