Copy Number Alterations Associated with Acute Lymphoblastic Leukemia in Mexican Children. A report from The Mexican Inter-Institutional Group for the identification of the causes of childhood leukemia

Rosales-Rodríguez, Beatriz; Fernández-Ramírez, Fernando; Núñez-Enríquez, Juan Carlos; Velázquez-Wong, Ana Claudia; Medina-Sansón, Aurora; Jiménez‐Hernández, Elva; Flores-Lujano, Janet; Peñaloza-González, José Gabriel; Espinosa-Elizondo, Rosa Martha; Pérez-Saldivar, María Luisa; Torres-Nava, José Refugio; Martín-Trejo, Jorge Alfonso; Martínez-Morales, Gabriela Bibiana; Bekker-Méndez, Carolina; Mejı́a-Aranguré, Juan Manuel; Rosas-Vargas, Haydeé

doi:10.1016/j.arcmed.2016.12.002

Cited by 9 publications

(8 citation statements)

References 22 publications

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“…THZ-P1-2 as a Probe for Potential PI5P4K Dependencies in Cancer PIP4K2A was found to be essential for cell survival in AML (Jude et al, 2014), and several variant SNPs in the PIP4K2A locus have been associated with ALL susceptibility and leukemogenesis (Rosales-Rodríguez, et al, 2016;Urayama et al, 2018). We evaluated the sensitivity of a small panel of leukemia cell lines to THZ-P1-2, using a 72-h CellTiter-Glo assay.…”

Section: Cellular Target Engagement and Kinome Selectivity Of Thz-p1-2mentioning

confidence: 99%

“…PIP4K2B-null mice were found to have increased insulin sensitivity and reduced adiposity (Lamia et al, 2004). PIP4K2A was found to be a dependency in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) (Jude et al, 2014;Rosales-Rodríguez, et al, 2016;Urayama et al, 2018) and PIP4K2A À/À , PIP4K2B +À , TP53 À/À mice had a dramatic tumor-free life extension compared with TP53 À/À mice, uncovering a potential synthetic lethality of PI5P4K with p53 (Emerling et al, 2013). Knockdown of PIP4K2A/B in human retinal pigment epithelial cells and rabbit models abrogated the pathogenesis of proliferative vitreoretinopathy (Ma et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors

Sivakumaren

Shim

Zhang

et al. 2020

Cell Chemical Biology

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Section: Cellular Target Engagement and Kinome Selectivity Of Thz-p1-2mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors

Sivakumaren

Shim

Zhang

et al. 2020

Cell Chemical Biology

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“…PIP4K2A was found to be essential for cell survival in AML (Jude et al, 2015) and several variant SNPs in the PIP4K2A locus have been associated with ALL susceptibility and leukemogenesis (Rosales-Rodríguez, et al, 2016;Urayama et al, 2018). We evaluated the sensitivity of a small panel of leukemia cell lines to THZ-P1-2, using a 72 h Cell-Titer Glo assay.…”

Section: Thz-p1-2 As a Probe For Potential Pi5p4k Dependencies In Cancermentioning

confidence: 99%

“…PIP4K2B-null mice were found to have increased insulin sensitivity and reduced adiposity (Lamia et al, 2004). PIP4K2A was found to be a dependency in AML and ALL (Jude et al, 2015;Rosales-Rodríguez, et al, 2016;Urayama et al, 2018) and PIP4K2A -/-, PIP4K2B +/-, TP53 -/mice had a dramatic tumor-free life extension compared to TP53 -/mice, uncovering a potential synthetic lethality of PI5P4K with p53 . Knockdown of PIP4K2A/B in human retinal pigment epithelial cells and rabbit models abrogated the pathogenesis of proliferative vitreoretinopathy (Ma et al, 2016).…”

Section: Introductionmentioning

confidence: 97%

Targeting the PI5P4K lipid kinase family in cancer using novel covalent inhibitors

Sivakumaren

Shim

Zhang

et al. 2019

Preprint

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The PI5P4Ks have been demonstrated to be important for cancer cell proliferation and other diseases. However, the therapeutic potential of targeting these kinases is understudied due to a lack of potent, specific small molecules available. Here we present the discovery and characterization of a novel pan-PI5P4K inhibitor, THZ-P1-2, that covalently targets cysteines on a disordered loop in PI5P4K//. THZ-P1-2 demonstrates cellular on-target engagement with limited off-targets across the kinome. AML/ALL cell lines were sensitive to THZ-P1-2, consistent with PI5P4K's reported role in leukemogenesis. THZ-P1-2 causes autophagosome clearance defects and upregulation in TFEB nuclear localization and target genes, disrupting autophagy in a covalent-dependent manner and phenocopying the effects of PI5P4K genetic deletion. Our studies demonstrate that PI5P4Ks are tractable targets, with THZ-P1-2 as a useful tool to further interrogate the therapeutic potential of PI5P4K inhibition and inform drug discovery campaigns for these lipid kinases in cancer metabolism and other autophagy-dependent disorders.

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“…This duplication was present in 78% of cases of relapse patients and also in 15% of patients at initial diagnosis [ 164 ]. Furthermore, another chromosomal aberration such as 9p deletion associated with MTAP , CDKN2A , CDKN2B , DMRTA1 , and FLJ35282 gene loss was indicated [ 165 ]. In addition, it was suggested that environmental factors, such as infection, may also be linked with B-ALL development [ 166 ].…”

Section: Genetic Biomarkersmentioning

confidence: 99%

Genetic Biomarkers and Their Clinical Implications in B-Cell Acute Lymphoblastic Leukemia in Children

Lejman

Chałupnik

Chilimoniuk

et al. 2022

IJMS

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Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies characterized by abnormal proliferation of immature lymphoid cells. It is the most commonly diagnosed childhood cancer with an almost 80% cure rate. Despite favorable survival rates in the pediatric population, a significant number of patients develop resistance to therapy, resulting in poor prognosis. ALL is a heterogeneous disease at the genetic level, but the intensive development of sequencing in the last decade has made it possible to broaden the study of genomic changes. New technologies allow us to detect molecular changes such as point mutations or to characterize epigenetic or proteomic profiles. This process made it possible to identify new subtypes of this disease characterized by constellations of genetic alterations, including chromosome changes, sequence mutations, and DNA copy number alterations. These genetic abnormalities are used as diagnostic, prognostic and predictive biomarkers that play an important role in earlier disease detection, more accurate risk stratification, and treatment. Identification of new ALL biomarkers, and thus a greater understanding of their molecular basis, will lead to better monitoring of the course of the disease. In this article, we provide an overview of the latest information on genomic alterations found in childhood ALL and discuss their impact on patients’ clinical outcomes.

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Copy Number Alterations Associated with Acute Lymphoblastic Leukemia in Mexican Children. A report from The Mexican Inter-Institutional Group for the identification of the causes of childhood leukemia

Cited by 9 publications

References 22 publications

Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors

Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors

Targeting the PI5P4K lipid kinase family in cancer using novel covalent inhibitors

Genetic Biomarkers and Their Clinical Implications in B-Cell Acute Lymphoblastic Leukemia in Children

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