Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia

Oshima, Koichi; Zhao, Junfei; Pérez-Durán, Pablo; Brown, Jessie; Patiño-Galindo, Juan Ángel; Chu, Timothy; Quinn, S. Aidan; Gunning, Thomas; Belver, Laura; Ambesi-Impiombato, Alberto; Tosello, Valeria; Wang, Zhengqiang; Sulis, Maria Luisa; Kato, Motohiro; Koh, Katsuyoshi; Paganin, Maddalena; Basso, Giuseppe; Balbı́n, Milagros; Nicolás, Concepción; Gastier‐Foster, Julie M.; Devidas, Meenakshi; Loh, Mignon L.; Paietta, Elisabeth; Tallman, Martin S.; Rowe, Jacob M.; Litzow, Mark R.; Minden, Mark D.; Meijerink, Jules P.P.; Rabadán, Raúl; Ferrando, Adolfo A.

doi:10.1038/s43018-020-00124-1

Cited by 49 publications

(62 citation statements)

References 69 publications

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“…Druggable events vary between primary and relapse tumors. Only 37% of primary tumors retained these events upon progression whilst most tumors gained events, as reported in disease-specific reports [32,33,[77][78][79][80][81][82][83][84] These substantial spatiotemporal differences in the molecular profiles of multiple samples acquired from the same patient as well as metastases compared to primary tumors indicate the need for subsequent analyses to optimize biomarker-driven selection in clinical trial recruitment [39].…”

Section: Patient Accrualmentioning

confidence: 87%

The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development

Langenberg

Looze

Molenaar

2021

Cancers

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Over the last years, various precision medicine programs have been developed for pediatric patients with high-risk, relapsed, or refractory malignancies, selecting patients for targeted treatment through comprehensive molecular profiling. In this review, we describe characteristics of these initiatives, demonstrating the feasibility and potential of molecular-driven precision medicine. Actionable events are identified in a significant subset of patients, although comparing results is complicated due to the lack of a standardized definition of actionable alterations and the different molecular profiling strategies used. The first biomarker-driven trials for childhood cancer have been initiated, but until now the effect of precision medicine on clinical outcome has only been reported for a small number of patients, demonstrating clinical benefit in some. Future perspectives include the incorporation of novel approaches such as liquid biopsies and immune monitoring as well as innovative collaborative trial design including combination strategies, and the development of agents specifically targeting aberrations in childhood malignancies.

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Section: Patient Accrualmentioning

confidence: 87%

The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development

Langenberg

Looze

Molenaar

2021

Cancers

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“…While sample sizes are small, patients with T-ALL harboring PHF6 mutations tend to be older, have been demonstrated to have lower white blood cell counts than other T-ALL patients, as well as lower hemoglobin and platelet levels, splenomegaly/lymphadenopathy, and have blasts with a tendency to express CD13 ( 26 , 29 , 37 ). Genomic analysis of matched diagnosis, germline (remission) and relapse DNA samples from 46 T-ALL cases reveals that PHF6 alterations are found commonly at diagnosis, and persist at relapse ( 49 ). While mutations in PHF6 have been implicated in increased resistance to prednisolone in T-ALL cell lines, the majority of studies have shown no correlation with PHF6 mutations and overall survival in patients with T-ALL, and a potential favorable prognosis associated with T-LBL ( 4 , 26 , 27 , 29 , 50 , 51 ).…”

Section: Phf6 and Hematologic Diseasementioning

confidence: 99%

PHF6 Mutations in Hematologic Malignancies

Kurzer

Weinberg

2021

Front. Oncol.

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Next generation sequencing has uncovered several genes with associated mutations in hematologic malignancies that can serve as potential biomarkers of disease. Keeping abreast of these genes is therefore of paramount importance in the field of hematology. This review focuses on PHF6, a highly conserved epigenetic transcriptional regulator that is important for neurodevelopment and hematopoiesis. PHF6 serves as a tumor suppressor protein, with PHF6 mutations and deletions often implicated in the development of T-lymphoblastic leukemia and less frequently in acute myeloid leukemia and other myeloid neoplasms. PHF6 inactivation appears to be an early event in T-lymphoblastic leukemogenesis, requiring cooperating events, including NOTCH1 mutations or overexpression of TLX1 and TLX3 for full disease development. In contrast, PHF6 mutations tend to occur later in myeloid malignancies, are frequently accompanied by RUNX1 mutations, and are often associated with disease progression. Moreover, PHF6 appears to play a role in lineage plasticity within hematopoietic malignancies, with PHF6 mutations commonly present in mixed phenotype acute leukemias with a predilection for T-lineage marker expression. Due to conflicting data, the prognostic significance of PHF6 mutations remains unclear, with a subset of studies showing no significant difference in outcomes compared to malignancies with wild-type PHF6, and other studies showing inferior outcomes in certain patients with mutated PHF6. Future studies are necessary to elucidate the role PHF6 plays in development of T-lymphoblastic leukemia, progression of myeloid malignancies, and its overall prognostic significance in hematopoietic neoplasms.

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“…The simplicity and affordability of the MEMIC makes it compatible with mid- to high-throughput experiments and screens. Most chemotherapy drugs target rapidly proliferating cells, whereas senescent and non-proliferating tumor cells are spared, leading to lower tumor regression and relapse ( Gordon and Nelson, 2012 ; Oshima et al, 2020 ). Thus, the MEMIC could be particularly useful for screening drugs that more efficiently target ischemic regions of tumors in which non-proliferating cells are abundant.…”

Section: Discussionmentioning

confidence: 99%

“…The simplicity and affordability of the MEMIC makes it compatible with mid-to highthroughput experiments and screens. Most chemotherapy drugs target rapidly proliferating cells, while senescent and non-proliferating tumor cells are spared, leading to lower tumor regression and relapse (Gordon and Nelson, 2012;Oshima et al, 2020).…”

Section: Ischemic Macrophages Decrease Epithelial Features In Neighboring Tumor Cellsmentioning

confidence: 99%

The MEMIC is an ex vivo system to model the complexity of the tumor microenvironment

Janská

Anandi

Kirchberger

et al. 2021

Disease Models &Amp; Mechanisms

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There is an urgent need for accurate, scalable, and cost-efficient experimental systems to model the complexity of the tumor microenvironment. Here, we detail how to fabricate and use the Metabolic Microenvironment Chamber (MEMIC) – a 3D-printed ex vivo model of intratumoral heterogeneity. A major driver of the cellular and molecular diversity in tumors is the accessibility to the blood stream that provides key resources such as oxygen and nutrients. While some tumor cells have direct access to these resources, many others must survive under progressively more ischemic environments as they reside further from the vasculature. The MEMIC is designed to simulate the differential access to nutrients and allows co-culturing different cell types, such as tumor and immune cells. This system is optimized for live imaging and other microscopy-based approaches, and it is a powerful tool to study tumor features such as the effect of nutrient scarcity on tumor-stroma interactions. Due to its adaptable design and full experimental control, the MEMIC provide insights into the tumor microenvironment that would be difficult to obtain via other methods. As a proof of principle, we show that cells sense gradual changes in metabolite concentration resulting in multicellular spatial patterns of signal activation and cell proliferation. To illustrate the ease of studying cell-cell interactions in the MEMIC, we show that ischemic macrophages reduce epithelial features in neighboring tumor cells. We propose the MEMIC as a complement to standard in vitro and in vivo experiments, diversifying the tools available to accurately model, perturb, and monitor the tumor microenvironment, as well as to understand how extracellular metabolites affect other processes such as wound healing and stem cell differentiation.

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Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia

Cited by 49 publications

References 69 publications

The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development

The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development

PHF6 Mutations in Hematologic Malignancies

The MEMIC is an ex vivo system to model the complexity of the tumor microenvironment

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