Patient-derived induced pluripotent stem cells recapitulate hematopoietic abnormalities of juvenile myelomonocytic leukemia

Gandre-Babbe, Shilpa; Paluru, Prasuna; Aribeana, Chiaka; Chou, Stella T.; Bresolin, Silvia; Lin, Li; Sullivan, Spencer K.; Tasian, Sarah K.; Weng, Julie; Favre, H.; Choi, John K.; French, Deborah L.; Loh, Mignon L.; Weiss, Mitchell J.

doi:10.1182/blood-2013-01-478412

Cited by 105 publications

(124 citation statements)

References 25 publications

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“…47,48 Most recently, induced pluripotent stem cells (iPSCs) from malignant cells of 2 JMML patients with somatic heterozygous p.E76K missense mutations in PTPN11 have been generated. 49 In vitro differentiation of iPSCs produced myeloid cells with increased proliferative capacity, constitutive activation of GM-CSF, and enhanced STAT5/ERK phosphorylation, similar to what has been seen in primary JMML cells. Furthermore, pharmacological inhibition of MEK kinase in iPSC-derived JMML cells reduced their GM-CSF independence.…”

Section: Cell Culture Studies and Induced Pluripotent Stem Cellsmentioning

confidence: 61%

RAS diseases in children

Niemeyer

2014

Haematologica

127

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REVIEW ARTICLES 1653 IntroductionDiscoveries made about 50 years ago revealed the transforming power of the Harvey and Kirsten murine sarcoma retroviruses by a set of genes named RAS genes for their role in forming rat sarcomas. Subsequently, the contribution of RAS genes to cancer pathogenesis has been studied extensively. While the somatic dysregulation of RAS is a primary driver of cancer, there is a class of developmental disorders caused by germline mutations (as opposed to the somatic mutations found in cancer) in genes that encode components of the RAS signaling pathway. This chapter summarizes hematologic disturbances and cancer predisposition of these genetic disorders named "RASopathies". It will focus on juvenile myelomonocytic leukemia (JMML), an infant leukemia with initiating germline and somatic mutations in genes of the RAS signal transduction pathway. RAS and the RAS/mitogen-activated protein kinase signaling cascadeRAS turned out to be an essential cellular hub for a wide variety of signaling pathways including the three human RAS genes, KRAS, NRAS and HRAS (reviewed by Stephen et al. 1). RAS proteins act as molecular switches by cycling between an active guanosine triphospate (GTP)-bound (RAS-GTP) and an inactive guanosine diphosphate (GDP)-bound (RAS-GDP) conformation (Figure 1).2 RAS-GTP concentrations are tightly regulated by the competitive action of guanosin exchange factors (GEFs) and GTPase activating proteins (GAPs).RAS is activated by extracellular stimuli such as growth factor binding to receptor tyrosine kinases (RTKs) followed by RTK autophosphorylation and the creation of docking sites for adaptor molecules (e.g. GRB2). These molecules recruit and activate GEFs (e.g. SOS1) which displace GDP from RAS allowing RAS to bind to GTP. RAS-GTP binds to and activates a large number of effector pathways. The RAS-mediated mitogen-activated kinase (MAPK) pathway is one of several important downstream cascades. Activated RAS binds to RAF (RAF1, also known as CRAF, BRAF), the first MAPK of the signaling cascade. RAF phosphorylates MEK1 and/or MEK2, which in turn activate ERK1 and/or ERK2. Active ERKs serve as regulators of a large number of downstream processes both in the cytosol and nucleus.

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Section: Cell Culture Studies and Induced Pluripotent Stem Cellsmentioning

confidence: 61%

RAS diseases in children

Niemeyer

2014

Haematologica

127

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“…Generation of iPSCs from other cancer types is necessary to develop relevant in vitro models for carcinogenesis. [73] , 2013 CML iPSCs from CML cell lines and primary patient samples Carette et al [70] , 2010 Kumano et al [72] , 2012 JML Derived iPSCs from 2 JML patients Gandre-Babbe et al [75] , 2013 Gastrointestinal cancer Generated iPSCs from multiple GI cancer cell lines Miyoshi et al [69] , 2010 Glioblastoma iPSCs generated from glioblastoma-derived neural stem cells Stricker et al [76] , 2014; Stricker et al [77] , 2013…”

Section: Resultsmentioning

confidence: 99%

“…Cells were able to differentiate to myeloid cells which showed phenotypic similarities to the primary tumours including enhanced proliferation, suggesting they could be a useful resource to model the disease [75] .…”

Section: Ipscs and Juvenile Myelomonocytic Leukemiamentioning

confidence: 99%

Using induced pluripotent stem cells as a tool for modelling carcinogenesis

Curry

Moad

Robson

et al. 2015

WJSC

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Cancer is a highly heterogeneous group of diseases that despite improved treatments remain prevalent accounting for over 14 million new cases and 8.2 million deaths per year. Studies into the process of carcinogenesis are limited by lack of appropriate models for the development and pathogenesis of the disease based on human tissues. Primary culture of patient samples can help but is difficult to grow for a number of tissues. A potential opportunity to overcome these barriers is based on the landmark study by Yamanaka which demonstrated the ability of four factors; Oct4, Sox2, Klf4, and c-Myc to reprogram human somatic cells in to pluripotency. These cells were termed induced pluripotent stem cells (iPSCs) and display characteristic properties of embryonic stem cells. This technique has a wide range of potential uses including disease modelling, drug testing and transplantation studies. Interestingly iPSCs also share a number of characteristics with cancer cells including self-renewal and proliferation, expression of stem cell markers and altered metabolism. Recently, iPSCs have been generated from a number of human cancer cell lines and primary tumour samples from a range of cancers in an attempt to recapitulate the development of cancer and interrogate the underlying mechanisms involved. This review will outline the similarities between the reprogramming process and carcinogenesis, and how these similarities have been exploited to generate iPSC models for a number of cancers. Core tip: Human induced pluripotent stem cells (iPSCs) represent a novel method for studying the mechanisms of cancer development and progression. Recently, a number of studies have generated iPSCs from human cancer cells and cell lines, which can then be used as a model for carcinogenesis. This review outlines the similarities that exist between pluripotent and malignant cells and summarizes available studies that have generated iPSC models of cancer.

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“…9,10,16,17 Furthermore, induced pluripotent stem cells, generated from two patients with JMML, differentiated into myeloid cells with high proliferative capacity and enhanced basal ERK (a well-known mediator of RAS activation) and STAT5 activation. 18 Malignant cells from JMML patients and JMML mouse models display hypersensitivity to certain cytokines, in particular granulocyte-macrophage colony-stimulating factor (GM-CSF). 5,9,14,19 The absence of GM-CSF receptor signaling prevents the development of MPN in recipient mice receiving hematopoietic stem cells doubly deficient for Nf1 and the GM-CSF receptor common β chain.…”

Section: Stat5 Is Critical For the Development And Maintenance Of Myementioning

confidence: 99%

Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency

et al. 2016

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Patient-derived induced pluripotent stem cells recapitulate hematopoietic abnormalities of juvenile myelomonocytic leukemia

Abstract: Key Points Patient-derived iPSCs recapitulate juvenile myelomonocytic leukemia. MEK inhibition normalizes GM-CSF independence and hypersensitivity in myeloid precursors from JMML iPSCs.

Cited by 105 publications

References 25 publications

RAS diseases in children

RAS diseases in children

Using induced pluripotent stem cells as a tool for modelling carcinogenesis

Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency

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