ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype of acute lymphoblastic leukemia (ALL) with gradually improved survival through introduction of intensified chemotherapy. However, therapy-resistant or refractory T-ALL remains a major clinical challenge. Here, we evaluated B-cell lymphoma (BCL)-2 inhibition by the BH3 mimetic ABT-199 as a new therapeutic strategy in humanT-ALL. The T-ALL cell line LOUCY, which shows a transcriptional program related to immature T-ALL, exhibited high in vitro and in vivo sensitivity for ABT-199 in correspondence with high levels of BCL-2. In addition, ABT-199 showed synergistic therapeutic effects with different chemotherapeutic agents including doxorubicin, L-asparaginase, and dexamethasone. Furthermore, in vitro analysis of primary patient samples indicated that some immature, TLX3-orHOXA-positive primary T-ALLs are highly sensitive to BCL-2 inhibition, whereas TAL1 driven tumors mostly showed poor ABT-199 responses. Because BCL-2 shows high expression in early T-cell precursors and gradually decreases during normal T-cell differentiation, differences in ABT-199 sensitivity could partially be mediated by distinct stages of differentiation arrest between different molecular genetic subtypes of human T-ALL. In conclusion, our study highlights BCL-2 as an attractive molecular target in specific subtypes of human T-ALL that could be exploited by ABT-199

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

“…Several patients with T-ALL responded to venetoclax in vitro with IC 50 values in the nanomolar range ( Figure 5A), consistent with reports describing activity in early thymic precursor ALL and T-ALL. [40][41][42] These results were verified by flow cytometry using 7-aminoactinomycin D staining to quantify cell death (supplemental Figure 7). As expected, the response to oral administration of venetoclax in vivo correlated with in vitro activity for 3 T-ALL patients with strong, intermediate, and low venetoclax sensitivity.…”

Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia

“…Western blot analysis was performed as previously described (8). The primary antibodies used were Bcl-2 antibody (C-2) (1:500, Santa Cruz Biotechnology, Dallas, TX, USA; sc-7382), PARP-1 antibody (F-2)…”

“…Recently, we and other research groups reported promising therapeutic activity for venetoclax (ABT-199), a highly specific inhibitor of the anti-apoptotic protein BCL-2, in immature subtypes of human T-ALL (8)(9)(10). Nevertheless, venetoclax sensitivity is variable between different T-ALL patient samples and the emergence of resistance to venetoclax (11)(12)(13) as well as the occurrence of dose-limiting toxicities (14) provides a rationale for the evaluation of venetoclax as part of a combination therapy.…”

“…Indeed, previous studies have shown that venetoclax can synergize with conventional chemotherapeutic agents in human T-ALL, including doxorubicin, L-asparaginase, dexamethasone and cytarabine (8,9). Venetoclax has recently also been approved by the FDA for the treatment of chronic lymphocytic leukemia (CLL).…”

A Sanctuary for cancer cells: Microenvironment in T-cell acute lymphoblastic leukemia survival and drug resistance

“…It is important to note that bcl-2 is highly expressed in early T-cell precursors and gradually decreases during normal T-cell differentiation. The response to ABT-199 has also proven effective in preclinical xenograft models of immature T-ALL and its combination with conventional chemotherapy displayed higher synergism providing a rationale for including this compound in clinical arenas [67]. Various small inhibitors as well as blocking antibodies against Wnt ligands or receptors have been synthesized and tested with promising anti-tumor activity [68][69][70].…”