Constitutive Ras signaling and Ink4a/Arf inactivation cooperate during the development of B-ALL in mice

Sewastianik, Tomasz; Jiang, Meng; Sukhdeo, Kumar; Patel, Sanjay; Roberts, Kathryn G.; Kang, Yue; Alduaij, Ahmad; Dennis, Peter S.; Lawney, Brian; Liu, Ruiyang; Song, Ze–Zhou; Xiong, Jessie; Zhang, Yunyu; Lemieux, Madeleine E.; Pinkus, Geraldine S.; Rich, Jeremy; Weinstock, David M.; Mullighan, Charles G.; Sharpless, Norman E.; Carrasco, Ruben D.

doi:10.1182/bloodadvances.2017012211

Cited by 11 publications

(9 citation statements)

References 73 publications

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“…One study hypothesized that loss of USP9X (seen in 4/17 CRLF2-rearranged cases), which encodes a deubiquitinase known to stabilize activated JAK2, may naturally buffer the toxic effect of JAK/STAT signaling hyperactivation in DS-ALL [67]. In addition, activating mutations in signaling effectors have been shown to functionally cooperate with loss of Ink4a/Arf and Pax5 alterations to drive B-cell leukemia development in vivo [75,76].…”

Section: Somatic Alterations Found In Ds-allmentioning

confidence: 99%

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

2020

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Structural and numerical alterations of chromosome 21 are extremely common in hematological malignancies. While the functional impact of chimeric transcripts from fused chromosome 21 genes such as TEL-AML1, AML1-ETO, or FUS-ERG have been extensively studied, the role of gain of chromosome 21 remains largely unknown. Gain of chromosome 21 is a frequently occurring aberration in several types of acute leukemia and can be found in up to 35% of cases. Children with Down syndrome (DS), who harbor constitutive trisomy 21, highlight the link between gain of chromosome 21 and leukemogenesis, with an increased risk of developing acute leukemia compared with other children. Clinical outcomes for DS-associated leukemia have improved over the years through the development of uniform treatment protocols facilitated by international cooperative groups. The genetic landscape has also recently been characterized, providing an insight into the molecular pathogenesis underlying DS-associated leukemia. These studies emphasize the key role of trisomy 21 in priming a developmental stage and cellular context susceptible to transformation, and have unveiled its cooperative function with additional genetic events that occur during leukemia progression. Here, using DS-leukemia as a paradigm, we aim to integrate our current understanding of the role of trisomy 21, of critical dosage-sensitive chromosome 21 genes, and of associated mechanisms underlying the development of hematological malignancies. This review will pave the way for future investigations on the broad impact of gain of chromosome 21 in hematological cancer, with a view to discovering new vulnerabilities and develop novel targeted therapies to improve long term outcomes for DS and non-DS patients.

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Section: Somatic Alterations Found In Ds-allmentioning

confidence: 99%

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

2020

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“…In numerous in vitro and in vivo systems, RAS alleles have been shown genetically and biochemically interact with both INK4A and ARF [72,73,74]. Specifically, Ink4a and/or Arf deficiency effectively cooperates with mutant Kras G12D alleles in promoting tumors in several mouse models [75,76]. In the context of PDAC pathogenesis, it should be important to determine what signals, if any, provoke INK4A and ARF expression in PanIN of various stages, and to identify specific roles of either gene in restraining PanIN progression.…”

Section: Modeling Cell Cycle Inhibitors Ink4a/arf Loss In Pdacmentioning

confidence: 99%

The Use of Genetically Engineered Mouse Models for Studying the Function of Mutated Driver Genes in Pancreatic Cancer

Weng

Lin

Cheng

2019

JCM

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Pancreatic cancer is often treatment-resistant, with the emerging standard of care, gemcitabine, affording only a few months of incrementally-deteriorating survival. Reflecting on the history of failed clinical trials, genetically engineered mouse models (GEMMs) in oncology research provides the inspiration to discover new treatments for pancreatic cancer that come from better knowledge of pathogenesis mechanisms, not only of the derangements in and consequently acquired capabilities of the cancer cells, but also in the aberrant microenvironment that becomes established to support, sustain, and enhance neoplastic progression. On the other hand, the existing mutational profile of pancreatic cancer guides our understanding of the disease, but leaves many important questions of pancreatic cancer biology unanswered. Over the past decade, a series of transgenic and gene knockout mouse modes have been produced that develop pancreatic cancers with features reflective of metastatic pancreatic ductal adenocarcinoma (PDAC) in humans. Animal models of PDAC are likely to be essential to understanding the genetics and biology of the disease and may provide the foundation for advances in early diagnosis and treatment.

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“…Immunohistochemistry. Four-micron-thick sections of formalin-fixed spleen tissues were stained with H&E, according to standard protocols (56); coimmunostained for PAX5 and CD5 expression, according to previously described methods (RD Carrasco, personal communication); or stained for Ki67 expression (57). Anti-PAX5 rabbit monoclonal antibody (clone D7H5X, used at 1:75 dilution) was purchased from Cell Signaling Technology, anti-CD5 rabbit polyclonal antibody (used at 1:300) was purchased from Sino Biological, and anti-Ki67 rabbit polyclonal antibody (used at 1:1,000) was purchased from Vector Laboratories.…”

Section: Gtgtggaggagctg-3′mentioning

confidence: 99%

Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies

Hacken¹,

Valentin²,

Regis³

et al. 2018

JCI Insight

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Constitutive Ras signaling and Ink4a/Arf inactivation cooperate during the development of B-ALL in mice

Abstract: Key Points• Ras pathway activation cooperates with Ink4a/Arf locus deletion in B cells to induce a fully penetrant lymphoma/leukemia phenotype in mice.• These tumors resemble high-risk subtypes of human B-ALL, providing a convenient and highly reproducible model of refractory B-ALL.

Cited by 11 publications

References 73 publications

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

The Use of Genetically Engineered Mouse Models for Studying the Function of Mutated Driver Genes in Pancreatic Cancer

Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies

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