Maturation Stage of T-cell Acute Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and Sensitivity to ABT-199

Abstract

Acute Lymphoblastic Leukemia (ALL) is a hematopoietic malignancy derived from immature B-and T-lymphoid cells (T-ALL). In T-ALL there is an early T-cell progenitor (ETP) subgroup that has a very high risk for relapse. In this study, we utilized mitochondrial BH3 profiling to determine anti-apoptotic dependencies in T-ALL. We found that T-ALL cell lines and primary patient samples are dependent upon BCL-XL, except when the cancer bears ETP phenotype, in which case it is BCL-2 dependent. These distinctions directly relate to differential sensitivity to the BH3 mimetics ABT-263 and ABT-199 both in vitro and in vivo. We thus describe for the first time a change of anti-apoptotic dependence that is related to the differentiation stage of the leukemic clone. Our findings demonstrate that BCL-2 is a clinically relevant target for therapeutic intervention with ABT-199 in ETP-ALL.

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

“…50 Supportive information using other biomarkers would be desirable for monitoring response in clinical trials. The BCL2:BCL-XL expression ratio was proposed as a predictive biomarker for venetoclax response, 44 but our results and other data 50 suggest that this approach may not detect all cases. BH3 profiling using synthetic peptides instead of targeted smallmolecule drugs 44,51,52 may provide complementary information, as evaluated in a phase 2 study that assessed venetoclax monotherapy in patients with refractory and relapsed AML.…”

“…The BCL2:BCL-XL expression ratio was proposed as a predictive biomarker for venetoclax response, 44 but our results and other data 50 suggest that this approach may not detect all cases. BH3 profiling using synthetic peptides instead of targeted smallmolecule drugs 44,51,52 may provide complementary information, as evaluated in a phase 2 study that assessed venetoclax monotherapy in patients with refractory and relapsed AML. 53 We propose that in vitro drug profiling be incorporated into upcoming clinical trials for venetoclax to determine its predictive potential.…”

“…The BCL2:BCL-XL and BCL2:MCL1 ratios were suggested as biomarkers for venetoclax sensitivity in ALL 44 and in multiple myeloma, 45 respectively. We determined levels of BCL2 family members by intracellular flow cytometry and western blotting ( Figure 5C; supplemental Figure 10).…”

Restraining FOXO3-dependent transcriptional BMF activation underpins tumour growth and metastasis of E-cadherin-negative breast cancer

“…41 Preclinical intervention strategies using BH3-only mimetics as monotherapy have been successful but mostly in lymphoid malignancies. 42,43 Recent studies indicated that BH3-mimetics can be used to treat nonlymphoid cancers but mostly in combination with oestrogen antagonists, proteasome inhibitors, specific PI3K-mTOR inhibitors or chemotherapy. 24,[44][45][46][47][48][49] As previous findings from our laboratory demonstrated that E-cadherin-negative lobular breast cancer depends on p120-catenin-mediated activation of RhoA, Rock and subsequent actomyosin contraction, 26 we anticipate that dual inhibition of these pathways might be successful in E-cadherin-negative cancers that are not driven by oncogenic activation of GFR pathways.…”

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

“…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.…”