RASopathies: From germline mutations to somatic and multigenic diseases

Riller, Quentin; Rieux-Laucat, Frédéric

doi:10.1016/j.bj.2021.06.004

Cited by 44 publications

(43 citation statements)

References 84 publications

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“…Interestingly, in some cases these syndromes are associated to a higher cancer predisposition, similar to what happens in K5-ERAS transgenic mice. In this context, ERAS adds up to the list of genes whose mutation can lead to overgrowth syndromes (as AKT , PIK3CA , PTEN ) or RASopathies (as H-RAS , RASA1 , NF1 and RAF1 , among others [ 44 ]).…”

Section: Discussionmentioning

confidence: 99%

ERAS, a Member of the Ras Superfamily, Acts as an Oncoprotein in the Mammary Gland

Suárez-Cabrera

Ojeda-Pérez

Sánchez-Baltasar

et al. 2021

Cancers

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ERAS is a relatively uncharacterized gene of the Ras superfamily. It is expressed in ES cells and in the first stages of embryonic development; later on, it is silenced in the majority of cell types and tissues. Although there are several reports showing ERAS expression in tumoral cell lines and human tumor samples, it is unknown if ERAS deregulated expression is enough to drive tumor development. In this report, we have generated transgenic mice expressing ERAS in myoepithelial basal cells of the mammary gland and in basal cells of stratified epithelia. In spite of the low level of ERAS expression, these transgenic mice showed phenotypic alterations resembling overgrowth syndromes caused by the activation of the AKT-PI3K pathway. In addition, their mammary glands present developmental and functional disabilities accompanied by morphological and biochemical alterations in the myoepithelial cells. These mice suffer from tumoral transformation in the mammary glands with high incidence. These mammary tumors resemble, both histologically and by the expression of differentiation markers, malignant adenomyoepitheliomas. In sum, our results highlight the importance of ERAS silencing in adult tissues and define a truly oncogenic role for ERAS in mammary gland cells when inappropriately expressed.

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Section: Discussionmentioning

confidence: 99%

ERAS, a Member of the Ras Superfamily, Acts as an Oncoprotein in the Mammary Gland

Suárez-Cabrera

Ojeda-Pérez

Sánchez-Baltasar

et al. 2021

Cancers

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“…ERK1/2 are activated by various extracellular triggers such as GPCRs, integrins, and receptor tyrosine kinases, and are responsible for the induction of cellular responses such as proliferation, differentiation, and cell survival. The cascade is involved in the development and progression of many diseases including cancer, heart failure, developmental diseases, and autoimmune diseases, but are also vital for many physiological effects such as protection from cell death [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Despite the many triggers that activate this central signaling cascade, it is unclear how ERK1/2 can transmit specific and controlled cellular responses.…”

Section: Erk1/2mentioning

confidence: 99%

Harnessing RKIP to Combat Heart Disease and Cancer

Lorenz

Rosner

2022

Cancers

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Cancer and heart disease are leading causes of morbidity and mortality worldwide. These diseases have common risk factors, common molecular signaling pathways that are central to their pathogenesis, and even some disease phenotypes that are interdependent. Thus, a detailed understanding of common regulators is critical for the development of new and synergistic therapeutic strategies. The Raf kinase inhibitory protein (RKIP) is a regulator of the cellular kinome that functions to maintain cellular robustness and prevent the progression of diseases including heart disease and cancer. Two of the key signaling pathways controlled by RKIP are the β-adrenergic receptor (βAR) signaling to protein kinase A (PKA), particularly in the heart, and the MAP kinase cascade Raf/MEK/ERK1/2 that regulates multiple diseases. The goal of this review is to discuss how we can leverage RKIP to suppress cancer without incurring deleterious effects on the heart. Specifically, we discuss: (1) How RKIP functions to either suppress or activate βAR (PKA) and ERK1/2 signaling; (2) How we can prevent cancer-promoting kinase signaling while at the same time avoiding cardiotoxicity.

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“…Over 90% of JMML driver mutations involve five genes in the canonical RAS pathway ( PTPN11, NRAS, KRAS, NF1 , CBL) , with approximately 35% being somatic PTPN11 (gain of SHP-2 function) exon 3 or 13 mutations [ 133 , 189 , 190 , 204 , 205 , 224 , 225 , 226 , 227 , 228 , 229 ]. Hypersensitivity of JMML progenitors to GM-CSF, IL3 and TNFa in vitro, hyperproliferation of monocytic and/or granulocytic lineages in vivo, thrombocytopenia, and increased fetal hemoglobin (HbF in 50–60% of patients) are common JMML features, with occasional transformation to ALL, suggesting a disease of, or expressed in, multipotent HSC/MPP [ 204 , 205 , 224 , 225 , 226 , 227 , 228 , 229 ]. A number of recent studies have investigated the cellular origin and clonal evolution of JMML using iPS cell [ 230 , 231 , 232 , 233 , 234 , 235 , 236 ] and xenograft models [ 237 , 238 , 239 ].…”

Section: Pediatric Aml and Juvenile Myelomonocytic Leukemia (Jmml)mentioning

confidence: 99%

Increasing Complexity of Molecular Landscapes in Human Hematopoietic Stem and Progenitor Cells during Development and Aging

Watt

Hua

Roberts

2022

IJMS

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The past five decades have seen significant progress in our understanding of human hematopoiesis. This has in part been due to the unprecedented development of advanced technologies, which have allowed the identification and characterization of rare subsets of human hematopoietic stem and progenitor cells and their lineage trajectories from embryonic through to adult life. Additionally, surrogate in vitro and in vivo models, although not fully recapitulating human hematopoiesis, have spurred on these scientific advances. These approaches have heightened our knowledge of hematological disorders and diseases and have led to their improved diagnosis and therapies. Here, we review human hematopoiesis at each end of the age spectrum, during embryonic and fetal development and on aging, providing exemplars of recent progress in deciphering the increasingly complex cellular and molecular hematopoietic landscapes in health and disease. This review concludes by highlighting links between chronic inflammation and metabolic and epigenetic changes associated with aging and in the development of clonal hematopoiesis.

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RASopathies: From germline mutations to somatic and multigenic diseases

Cited by 44 publications

References 84 publications

ERAS, a Member of the Ras Superfamily, Acts as an Oncoprotein in the Mammary Gland

ERAS, a Member of the Ras Superfamily, Acts as an Oncoprotein in the Mammary Gland

Harnessing RKIP to Combat Heart Disease and Cancer

Increasing Complexity of Molecular Landscapes in Human Hematopoietic Stem and Progenitor Cells during Development and Aging

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