BH3 profiling identifies BCL-2 dependence in adult patients with early T-cell progenitor acute lymphoblastic leukemia

Olesinski, Elyse A.; Bhatia, Karanpreet Singh; Mahesh, Aarthi Nivasini; Rosli, Shazwina; Mohamed, Jameelah S; Jen, Wei Ying; Jain, Nitin; Garcia, Jacqueline S.; Wong, Gee Chuan; Ooi, Melissa; Letai, Antony; Konopleva, Marina; Bhatt, Shruti

doi:10.1182/bloodadvances.2022007728

Cited by 4 publications

(1 citation statement)

References 24 publications

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“…In this project, we use new functional assays to create a drug response profile, including the DBP, which can predict which treatments will be most effective in eliminating a specific tumor. DBP has already been used to evaluate therapies in different types of cancer (22) and has been successfully tested in ALL (23)(24)(25)(26). In addition, we can execute this assay to identify antiapoptotic adaptations and use that information to design new therapeutic strategies for ALL, preventing it from becoming resistant and restoring its sensitivity to cell death.…”

Section: Dynamic Bh3 Profilingmentioning

confidence: 99%

The relapsed acute lymphoblastic leukemia network (ReALLNet): a multidisciplinary project from the spanish society of pediatric hematology and oncology (SEHOP)

Velasco,

Bautista,

Rubio

et al. 2023

Front. Pediatr.

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Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, with survival rates exceeding 85%. However, 15% of patients will relapse; consequently, their survival rates decrease to below 50%. Therefore, several research and innovation studies are focusing on pediatric relapsed or refractory ALL (R/R ALL). Driven by this context and following the European strategic plan to implement precision medicine equitably, the Relapsed ALL Network (ReALLNet) was launched under the umbrella of SEHOP in 2021, aiming to connect bedside patient care with expert groups in R/R ALL in an interdisciplinary and multicentric network. To achieve this objective, a board consisting of experts in diagnosis, management, preclinical research, and clinical trials has been established. The requirements of treatment centers have been evaluated, and the available oncogenomic and functional study resources have been assessed and organized. A shipping platform has been developed to process samples requiring study derivation, and an integrated diagnostic committee has been established to report results. These biological data, as well as patient outcomes, are collected in a national registry. Additionally, samples from all patients are stored in a biobank. This comprehensive repository of data and samples is expected to foster an environment where preclinical researchers and data scientists can seek to meet the complex needs of this challenging population. This proof of concept aims to demonstrate that a network-based organization, such as that embodied by ReALLNet, provides the ideal niche for the equitable and efficient implementation of “what's next” in the management of children with R/R ALL.

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Section: Dynamic Bh3 Profilingmentioning

confidence: 99%

The relapsed acute lymphoblastic leukemia network (ReALLNet): a multidisciplinary project from the spanish society of pediatric hematology and oncology (SEHOP)

Velasco,

Bautista,

Rubio

et al. 2023

Front. Pediatr.

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T-cell Acute Lymphoblastic Leukemia

Usman,

O’Dwyer

2024

Advances in Oncology

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Dual Targeting of Apoptotic and Signaling Pathways in T-Lineage Acute Lymphoblastic Leukemia

Saygin,

Giordano,

Shimamoto

et al. 2023

Clinical Cancer Research

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Purpose: Relapsed T-acute lymphoblastic leukemia (T-ALL) has limited treatment options. We investigated mechanisms of resistance to BH3 mimetics in T-ALL in order to develop rational combination strategies. We also looked at the preclinical efficacy of NWP-0476, a novel BCL-2/BCL-xL inhibitor, as single agent and combination therapy in T-ALL. Methods: We used BH3 profiling as a predictive tool for BH3 mimetic response in T-ALL. Using isogenic control, venetoclax-resistant (ven-R) and NWP-0476-resistant (NWP-R) cells, phosphokinase array was performed to identify differentially regulated signaling pathways. Results: Typical T-ALL cells had increased dependence on BCL-xL, while early T-precursor (ETP)-ALL cells had higher BCL-2 dependence for survival. BCL-2/BCL-xL dual inhibitors were effective against both subtypes of T-lineage ALL. A 71-protein human phosphokinase array showed increased LCK activity in ven-R cells, and increased ACK1 activity in ven-R and NWP-R cells. We hypothesized that pre-TCR and ACK1 signaling pathways are drivers of resistance to BCL-2 and BCL-xL inhibition, respectively. First, we silenced LCK gene in T-ALL cell lines, which resulted in increased sensitivity to BCL-2 inhibition. Mechanistically, LCK activated NF-κB pathway and the expression of BCL-xL. Silencing ACK1 gene resulted in increased sensitivity to both BCL-2 and BCL-xL inhibitors. ACK1 signaling up-regulated AKT pathway, which inhibited the pro-apoptotic function of BAD. In a T-ALL patient-derived xenograft model, combination of NWP-0476 and dasatinib demonstrated synergy without major organ toxicity. Conclusions:LCK and ACK1 signaling pathways are critical regulators of BH3 mimetic resistance in T-ALL. Combination of BH3 mimetics with tyrosine kinase inhibitors might be effective against relapsed T-ALL.

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BH3 profiling identifies BCL-2 dependence in adult patients with early T-cell progenitor acute lymphoblastic leukemia

Cited by 4 publications

References 24 publications

The relapsed acute lymphoblastic leukemia network (ReALLNet): a multidisciplinary project from the spanish society of pediatric hematology and oncology (SEHOP)

The relapsed acute lymphoblastic leukemia network (ReALLNet): a multidisciplinary project from the spanish society of pediatric hematology and oncology (SEHOP)

T-cell Acute Lymphoblastic Leukemia

Dual Targeting of Apoptotic and Signaling Pathways in T-Lineage Acute Lymphoblastic Leukemia

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