2018
DOI: 10.1038/s41375-018-0169-y
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Mutation-specific signaling profiles and kinase inhibitor sensitivities of juvenile myelomonocytic leukemia revealed by induced pluripotent stem cells

Abstract: Juvenile myelomonocytic leukemia (JMML) is an uncommon myeloproliferative neoplasm driven by Ras pathway mutations and hyperactive Ras/MAPK signaling. Outcomes for many children with JMML remain dismal with current standard-of-care cytoreductive chemotherapy and hematopoietic stem cell transplantation. We used patient-derived induced pluripotent stem cells (iPSCs) to characterize the signaling profiles and potential therapeutic vulnerabilities of PTPN11-mutant and CBL-mutant JMML. We assessed whether MEK, JAK,… Show more

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Cited by 48 publications
(69 citation statements)
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“…In addition, the cells that differentiate from iPSCs have embryonic phenotypes, not adult ones. To date, iPSCs have been used to study RASopathy pathogenesis in cardiomyocytes, neural cells, and blood cell types (Jaffre et al, 2019;Mulero-Navarro et al, 2015;Rooney et al, 2016;Tasian et al, 2019).…”
Section: Preclinical Rasopathy Models For Translational Studiesmentioning
confidence: 99%
See 1 more Smart Citation
“…In addition, the cells that differentiate from iPSCs have embryonic phenotypes, not adult ones. To date, iPSCs have been used to study RASopathy pathogenesis in cardiomyocytes, neural cells, and blood cell types (Jaffre et al, 2019;Mulero-Navarro et al, 2015;Rooney et al, 2016;Tasian et al, 2019).…”
Section: Preclinical Rasopathy Models For Translational Studiesmentioning
confidence: 99%
“…In addition, the cells that differentiate from iPSCs have embryonic phenotypes, not adult ones. To date, iPSCs have been used to study RASopathy pathogenesis in cardiomyocytes, neural cells, and blood cell types (Jaffre et al, ; Mulero‐Navarro et al, ; Rooney et al, ; Tasian et al, ). In the context of ART, we will attempt to create both fibroblast and iPSC lines from each participant who travels to the NIH Clinical Center.…”
Section: Introductionmentioning
confidence: 99%
“…Core oncogenic mutations occur in RAS genes HRAS , neuroblastoma RAS viral oncogene homolog (NRAS) , and Kirsten rat sarcoma viral oncogene homolog (KRAS) , among them KRAS exhibits the most prevalent mutations in human cancers (Adhikari and Counter, ; Ambrogio et al, ) in which it has been estimated that about 25% of all human cancers harbor KRAS oncogenic mutations (Sanclemente et al, ). HRAS oncogenic mutations are less common compared with the KRAS and NRAS (Tasian et al, ). KRAS gene encodes KRAS‐4A and KRAS‐4B proteins that are collectively termed KRAS (Adhikari and Counter, ).…”
Section: Mapk Signalingmentioning
confidence: 99%
“…PI3K reactivation is a common mechanism of acquired cancer cell resistance to therapy, and PI3K inhibitors can be used as a promising strategy for cancer cell sensitization to MAPK‐targeted therapies (Yan et al, ; Yen et al, ). Mutation of SHP2 encoder PTPN11 in leukemia is reported to cause constitutive activation of PI3K/mTOR and RAS/MAPK (Tasian et al, ) indicating that the two signaling have common upstream mediators, namely RAS proteins (Dietrich et al, ). PI3K is responsible for production of phosphatidylinositol (3,4,5)‐tris‐ phosphate (PIP3), a second messenger known to activate PDK1 and AKT protein kinases implicating in several tumor promoting activities including survival and metastasis (Sanclemente et al, ).…”
Section: Mapk Cross‐talking With Other Signaling Pathwaysmentioning
confidence: 99%
“…substrates independently of FLT3, such as JAK2,32,33 a possibility that warrants testing of targeted JAK2 inhibitors in cell growth assays and AKT/ERK/STAT signalling studies.Here, via a thorough and extensive comparison of the anti-leukaemic potential of a panel of FLT3 inhibitors that have either beenFDA approved (midostaurin and gilteritinib) or that are in late-stage clinical development (crenolanib, quizartinib and sorafenib), we show that all FLT3 inhibitors, regardless of their broad or narrow range of targeted activity, are potent inhibitors of growth of mutant CBL-positive leukaemia, with some, like crenolanib, gilteritinib and midostaurin, showing more activity than others against primary mutant CBL-positive leukaemia. FLT3 inhibitors at a concentration of 1000 nmol/L were effective in inhibiting growth of primary AML and CMML cells harbouring not only mutant CBL, but also other oncogenes, including ASXL1, RUNX1, IDH2, SRSF2, STAG2, AXL1 and TET2 (Table S1).…”
mentioning
confidence: 99%