Loading...
Please wait, while we are loading the content...
Similar Documents
Cotargeting BCL-2 and MCL-1 in high-risk B-ALL
| Content Provider | Scilit |
|---|---|
| Author | Moujalled, Donia M. Hanna, Diane T. Hediyeh-Zadeh, Soroor Pomilio, Giovanna Brown, Lauren Litalien, Veronique Bartolo, Ray Fleming, Shaun Chanrion, Maïa Banquet, Sébastien Maragno, Ana-Leticia Kraus-Berthier, Laurence Schoumacher, Marie Mullighan, Charles G. Georgiou, Angela White, Christine A. Lessene, Guillaume Huang, David C. S. Roberts, Andrew W. Geneste, Olivier Rasmussen, Lorna Davis, Melissa J. Ekert, Paul G. Wei, Andrew Ng, Ashley P. Khaw, Seong L. |
| Copyright Year | 2020 |
| Description | Improving survival outcomes in adult B-cell acute lymphoblastic leukemia (B-ALL) remains a clinical challenge. Relapsed disease has a poor prognosis despite the use of tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome positive (Ph+ ALL) cases and immunotherapeutic approaches, including blinatumomab and chimeric antigen receptor T cells. Targeting aberrant cell survival pathways with selective small molecule BH3-mimetic inhibitors of BCL-2 (venetoclax, S55746), BCL-XL (A1331852), or MCL1 (S63845) is an emerging therapeutic option. We report that combined targeting of BCL-2 and MCL1 is synergistic in B-ALL in vitro. The combination demonstrated greater efficacy than standard chemotherapeutics and TKIs in primary samples from adult B-ALL with Ph+ ALL, Ph-like ALL, and other B-ALL. Moreover, combined BCL-2 or MCL1 inhibition with dasatinib showed potent killing in primary Ph+ B-ALL cases, but the BH3-mimetic combination appeared superior in vitro in a variety of Ph-like ALL samples. In PDX models, combined BCL-2 and MCL1 targeting eradicated ALL from Ph− and Ph+ B-ALL cases, although fatal tumor lysis was observed in some instances of high tumor burden. We conclude that a dual BH3-mimetic approach is highly effective in diverse models of high-risk human B-ALL and warrants assessment in clinical trials that incorporate tumor lysis precautions. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322969/pdf |
| Ending Page | 2767 |
| Page Count | 6 |
| Starting Page | 2762 |
| DOI | 10.1182/bloodadvances.2019001416 |
| Journal | Blood advances |
| Issue Number | 12 |
| Volume Number | 4 |
| Language | English |
| Publisher | American Society of Hematology |
| Publisher Date | 2020-06-22 |
| Access Restriction | Open |
| Subject Keyword | Hematology Research and Experimental Medicine Survival Models Efficacy Adult Antigen Mcl1 Diverse Bcl Mimetic Bh3 Journal: Blood advances (Vol- 118, Issue- 12) |
| Content Type | Text |
| Resource Type | Article |
