The Experts below are selected from a list of 1023 Experts worldwide ranked by ideXlab platform
Charlotte M. Niemeyer - One of the best experts on this subject based on the ideXlab platform.
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circrnas dysregulated in Juvenile Myelomonocytic Leukemia circmctp1 stands out
Frontiers in Cell and Developmental Biology, 2021Co-Authors: Anna Dal Molin, Charlotte M. Niemeyer, Christian Flotho, Jan Stary, Mattias Hofmans, Helene Cave, Enrico Gaffo, Alessia Buratin, Valerie De Haas, Pieter Van VlierbergheAbstract:Juvenile Myelomonocytic Leukemia (JMML), a rare myelodysplastic/myeloproliferative neoplasm of early childhood, is characterized by clonal growth of RAS signaling addicted stem cells. JMML subtypes are defined by specific RAS pathway mutations and display distinct gene, microRNA (miRNA) and long non-coding RNA expression profiles. Here we zoom in on circular RNAs (circRNAs), molecules that, when abnormally expressed, may participate in malignant deviation of cellular processes. CirComPara software was used to annotate and quantify circRNAs in RNA-seq data of a "discovery cohort" comprising 19 JMML patients and 3 healthy donors (HD). In an independent set of 12 JMML patients and 6 HD, expression of 27 circRNAs was analyzed by qRT-PCR. CircRNA-miRNA-gene networks were reconstructed using circRNA function prediction and gene expression data. We identified 119 circRNAs dysregulated in JMML and 59 genes showing an imbalance of the circular and linear products. Our data indicated also circRNA expression differences among molecular subgroups of JMML. Validation of a set of deregulated circRNAs in an independent cohort of JMML patients confirmed the down-regulation of circOXNAD1 and circATM, and a marked up-regulation of circLYN, circAFF2, and circMCTP1. A new finding in JMML links up-regulated circMCTP1 with known tumor suppressor miRNAs. This and other predicted interactions with miRNAs connect dysregulated circRNAs to regulatory networks. In conclusion, this study provides insight into the circRNAome of JMML and paves the path to elucidate new molecular disease mechanisms putting forward circMCTP1 up-regulation as a robust example.
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Juvenile Myelomonocytic Leukemia who s the driver at the wheel
Blood, 2019Co-Authors: Charlotte M. Niemeyer, Christian FlothoAbstract:Juvenile Myelomonocytic Leukemia (JMML) is a unique clonal hematopoietic disorder of early childhood. It is classified as an overlap myeloproliferative/myelodysplastic neoplasm by the World Health Organization and shares some features with chronic Myelomonocytic Leukemia in adults. JMML pathobiology is characterized by constitutive activation of the Ras signal transduction pathway. About 90% of patients harbor molecular alterations in 1 of 5 genes (PTPN11, NRAS, KRAS, NF1, or CBL), which define genetically and clinically distinct subtypes. Three of these subtypes, PTPN11-, NRAS-, and KRAS-mutated JMML, are characterized by heterozygous somatic gain-of-function mutations in nonsyndromic children, whereas 2 subtypes, JMML in neurofibromatosis type 1 and JMML in children with CBL syndrome, are defined by germline Ras disease and acquired biallelic inactivation of the respective genes in hematopoietic cells. The clinical course of the disease varies widely and can in part be predicted by age, level of hemoglobin F, and platelet count. The majority of children require allogeneic hematopoietic stem cell transplantation for long-term Leukemia-free survival, but the disease will eventually resolve spontaneously in ∼15% of patients, rendering the prospective identification of these cases a clinical necessity. Most recently, genome-wide DNA methylation profiles identified distinct methylation signatures correlating with clinical and genetic features and highly predictive for outcome. Understanding the genomic and epigenomic basis of JMML will not only greatly improve precise decision making but also be fundamental for drug development and future collaborative trials.
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the long non coding rna landscape in Juvenile Myelomonocytic Leukemia
Haematologica, 2018Co-Authors: Mattias Hofmans, Charlotte M. Niemeyer, Henrik Hasle, Christian Flotho, Silvia Bresolin, Tim Lammens, Hetty Helsmoortel, Helene Cave, Marry M Van Den Heuveleibrink, Jan StaryAbstract:Juvenile Myelomonocytic Leukemia (JMML) is a rare and aggressive myelodysplastic and myeloproliferative disorder of early childhood. It is characterized by proliferation of granulocytic and monocytic cells.[1][1] Currently, hematopoietic stem cell transplantation (HSCT) is the standard of care and
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The mutational spectrum of PTPN11 in Juvenile Myelomonocytic Leukemia
2016Co-Authors: Noonan Syndrome/myeloproliferative Disease, Charlotte M. Niemeyer, Henrik Hasle, Peter D. Emanuel, Robert P. Castleberry, Mualla Cetin, Christian P Kratz, Gabriela KardosAbstract:mutations in PTPN11 occur in 35 % of pa-tients with de novo, nonsyndromic Juvenile Myelomonocytic Leukemia(JMML).Myelopro-liferative disorders (MPDs), either transient or more fulminant forms, can also occur in infants with NS (NS/MPD). We identified PTPN11 mutations in blood or bone marrow specimens from 77 newly reported patients with JMML (n 69) or NS/MPD (n 8). To-gether with previous reports, we compared the spectrum of PTPN11 mutations in 3 groups: (1) patients with JMML (n 107); (2) patients with NS/MPD (n 19); and (3) pa-tients with NS (n 243). Glu76 was the most commonlyaffectedresidue inJMML(n 45), with the Glu76Lys alteration (n 29) being most frequent. Eight of 19 patients with NS/ MPD carried the Thr73Ile substitution. These data suggest that there is a genotype/pheno-type correlation in the spectrum of PTPN11 mutations found in patients with JMML, NS/ MPD, and NS. This supports the need to characterize the spectrum of hematologic abnormalities in individuals with NS and to better define the impact of the PTPN11 lesion on the disease course in patients with NS
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How I treat Juvenile Myelomonocytic Leukemia
2016Co-Authors: How I Treat, Franco Locatelli, Charlotte M. NiemeyerAbstract:Juvenile Myelomonocytic Leukemia (JMML) is a unique, aggressive hematopoietic dis-order of infancy/early childhood caused by excessive proliferation of cells of mono-cytic and granulocytic lineages. Approxi-mately 90 % of patients carry either somatic or germline mutations of PTPN-11, K-RAS, N-RAS, CBL, or NF1 in their leukemic cells. These genetic aberrations are largely mutually exclusive and activate the Ras/mitogen-activated protein kinase pathway. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the therapy of choice for most patients with JMML, curing more than 50 % of affecte
Christian Flotho - One of the best experts on this subject based on the ideXlab platform.
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long non coding rnas as novel therapeutic targets in Juvenile Myelomonocytic Leukemia
Scientific Reports, 2021Co-Authors: Mattias Hofmans, Christian Flotho, Miriam Erlacher, Tim Lammens, Helene Cave, Barbara Depreter, Aurelie CayeAbstract:Juvenile Myelomonocytic Leukemia (JMML) treatment primarily relies on hematopoietic stem cell transplantation and results in long-term overall survival of 50–60%, demonstrating a need to develop novel treatments. Dysregulation of the non-coding RNA transcriptome has been demonstrated before in this rare and unique disorder of early childhood. In this study, we investigated the therapeutic potential of targeting overexpressed long non-coding RNAs (lncRNAs) in JMML. Total RNA sequencing of bone marrow and peripheral blood mononuclear cell preparations from 19 untreated JMML patients and three healthy children revealed 185 differentially expressed lncRNA genes (131 up- and 54 downregulated). LNA GapmeRs were designed for 10 overexpressed and validated lncRNAs. Molecular knockdown (≥ 70% compared to mock control) after 24 h of incubation was observed with two or more independent GapmeRs in 6 of them. For three lncRNAs (lnc-THADA-4, lnc-ACOT9-1 and NRIR) knockdown resulted in a significant decrease of cell viability after 72 h of incubation in primary cultures of JMML mononuclear cells, respectively. Importantly, the extent of cellular damage correlated with the expression level of the lncRNA of interest. In conclusion, we demonstrated in primary JMML cell cultures that knockdown of overexpressed lncRNAs such as lnc-THADA-4, lnc-ACOT9-1 and NRIR may be a feasible therapeutic strategy.
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circrnas dysregulated in Juvenile Myelomonocytic Leukemia circmctp1 stands out
Frontiers in Cell and Developmental Biology, 2021Co-Authors: Anna Dal Molin, Charlotte M. Niemeyer, Christian Flotho, Jan Stary, Mattias Hofmans, Helene Cave, Enrico Gaffo, Alessia Buratin, Valerie De Haas, Pieter Van VlierbergheAbstract:Juvenile Myelomonocytic Leukemia (JMML), a rare myelodysplastic/myeloproliferative neoplasm of early childhood, is characterized by clonal growth of RAS signaling addicted stem cells. JMML subtypes are defined by specific RAS pathway mutations and display distinct gene, microRNA (miRNA) and long non-coding RNA expression profiles. Here we zoom in on circular RNAs (circRNAs), molecules that, when abnormally expressed, may participate in malignant deviation of cellular processes. CirComPara software was used to annotate and quantify circRNAs in RNA-seq data of a "discovery cohort" comprising 19 JMML patients and 3 healthy donors (HD). In an independent set of 12 JMML patients and 6 HD, expression of 27 circRNAs was analyzed by qRT-PCR. CircRNA-miRNA-gene networks were reconstructed using circRNA function prediction and gene expression data. We identified 119 circRNAs dysregulated in JMML and 59 genes showing an imbalance of the circular and linear products. Our data indicated also circRNA expression differences among molecular subgroups of JMML. Validation of a set of deregulated circRNAs in an independent cohort of JMML patients confirmed the down-regulation of circOXNAD1 and circATM, and a marked up-regulation of circLYN, circAFF2, and circMCTP1. A new finding in JMML links up-regulated circMCTP1 with known tumor suppressor miRNAs. This and other predicted interactions with miRNAs connect dysregulated circRNAs to regulatory networks. In conclusion, this study provides insight into the circRNAome of JMML and paves the path to elucidate new molecular disease mechanisms putting forward circMCTP1 up-regulation as a robust example.
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Juvenile Myelomonocytic Leukemia who s the driver at the wheel
Blood, 2019Co-Authors: Charlotte M. Niemeyer, Christian FlothoAbstract:Juvenile Myelomonocytic Leukemia (JMML) is a unique clonal hematopoietic disorder of early childhood. It is classified as an overlap myeloproliferative/myelodysplastic neoplasm by the World Health Organization and shares some features with chronic Myelomonocytic Leukemia in adults. JMML pathobiology is characterized by constitutive activation of the Ras signal transduction pathway. About 90% of patients harbor molecular alterations in 1 of 5 genes (PTPN11, NRAS, KRAS, NF1, or CBL), which define genetically and clinically distinct subtypes. Three of these subtypes, PTPN11-, NRAS-, and KRAS-mutated JMML, are characterized by heterozygous somatic gain-of-function mutations in nonsyndromic children, whereas 2 subtypes, JMML in neurofibromatosis type 1 and JMML in children with CBL syndrome, are defined by germline Ras disease and acquired biallelic inactivation of the respective genes in hematopoietic cells. The clinical course of the disease varies widely and can in part be predicted by age, level of hemoglobin F, and platelet count. The majority of children require allogeneic hematopoietic stem cell transplantation for long-term Leukemia-free survival, but the disease will eventually resolve spontaneously in ∼15% of patients, rendering the prospective identification of these cases a clinical necessity. Most recently, genome-wide DNA methylation profiles identified distinct methylation signatures correlating with clinical and genetic features and highly predictive for outcome. Understanding the genomic and epigenomic basis of JMML will not only greatly improve precise decision making but also be fundamental for drug development and future collaborative trials.
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the long non coding rna landscape in Juvenile Myelomonocytic Leukemia
Haematologica, 2018Co-Authors: Mattias Hofmans, Charlotte M. Niemeyer, Henrik Hasle, Christian Flotho, Silvia Bresolin, Tim Lammens, Hetty Helsmoortel, Helene Cave, Marry M Van Den Heuveleibrink, Jan StaryAbstract:Juvenile Myelomonocytic Leukemia (JMML) is a rare and aggressive myelodysplastic and myeloproliferative disorder of early childhood. It is characterized by proliferation of granulocytic and monocytic cells.[1][1] Currently, hematopoietic stem cell transplantation (HSCT) is the standard of care and
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genome wide dna methylation is predictive of outcome in Juvenile Myelomonocytic Leukemia
Nature Communications, 2017Co-Authors: Elliot Stieglitz, Daniel B Lipka, Tali Mazor, Adam B. Olshen, Huimin Geng, Laura C. Gelston, Jon Akutagawa, Christoph Plass, Christian FlothoAbstract:Juvenile Myelomonocytic Leukemia (JMML) is a myeloproliferative disorder of childhood caused by mutations in the Ras pathway. Outcomes in JMML vary markedly from spontaneous resolution to rapid relapse after hematopoietic stem cell transplantation. Here, we hypothesized that DNA methylation patterns would help predict disease outcome and therefore performed genome-wide DNA methylation profiling in a cohort of 39 patients. Unsupervised hierarchical clustering identifies three clusters of patients. Importantly, these clusters differ significantly in terms of 4-year event-free survival, with the lowest methylation cluster having the highest rates of survival. These findings were validated in an independent cohort of 40 patients. Notably, all but one of 14 patients experiencing spontaneous resolution cluster together and closer to 22 healthy controls than to other JMML cases. Thus, we show that DNA methylation patterns in JMML are predictive of outcome and can identify the patients most likely to experience spontaneous resolution.
Jonathan A Epstein - One of the best experts on this subject based on the ideXlab platform.
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tie2 cre induced inactivation of a conditional mutant nf1 allele in mouse results in a myeloproliferative disorder that models Juvenile Myelomonocytic Leukemia
Pediatric Research, 2004Co-Authors: Aaron D Gitler, Warren S Pear, Yi Kong, John K Choi, Jonathan A EpsteinAbstract:Tie2-Cre–Induced Inactivation of a Conditional Mutant Nf1 Allele in Mouse Results in a Myeloproliferative Disorder that Models Juvenile Myelomonocytic Leukemia
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tie2 cre induced inactivation of a conditional mutant nf1 allele in mouse results in a myeloproliferative disorder that models Juvenile Myelomonocytic Leukemia
Pediatric Research, 2004Co-Authors: Aaron D Gitler, Warren S Pear, Yi Kong, John K Choi, Yuan Zhu, Jonathan A EpsteinAbstract:Neurofibromatosis type one (NF1) is a common genetic disorder affecting 1:4000 births and is characterized by benign and malignant tumors. Children with NF1 are predisposed to Juvenile Myelomonocytic Leukemia. The Nf1 gene encodes neurofibromin, which can function as a Ras GTPase-activating protein. Neurofibromin deficiency in mice leads to mid-gestation lethality due to cardiovascular defects. We have previously shown that conditional inactivation of Nf1 using Tie2-Cre recapitulates the heart defects seen in Nf1(-/-) embryos. Tie2-Cre transgenic mice express Cre recombinase in all endothelial cells. Here, we show that Tie2-Cre-mediated deletion of Nf1 also leads to excision of Nf1 in the hematopoietic lineage. Surviving mice exhibit a myeloproliferative disorder similar to Juvenile Myelomonocytic Leukemia seen in NF1 patients. These mice provide a useful model to study neurofibromin deficiency in hematopoiesis. Furthermore, defects in Tie2-Cre-expressing progenitors that result in heart and blood defects suggest that related heart and blood disorders in NF1 and other syndromes represent disorders of the hemangioblast.
Henrik Hasle - One of the best experts on this subject based on the ideXlab platform.
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the long non coding rna landscape in Juvenile Myelomonocytic Leukemia
Haematologica, 2018Co-Authors: Mattias Hofmans, Charlotte M. Niemeyer, Henrik Hasle, Christian Flotho, Silvia Bresolin, Tim Lammens, Hetty Helsmoortel, Helene Cave, Marry M Van Den Heuveleibrink, Jan StaryAbstract:Juvenile Myelomonocytic Leukemia (JMML) is a rare and aggressive myelodysplastic and myeloproliferative disorder of early childhood. It is characterized by proliferation of granulocytic and monocytic cells.[1][1] Currently, hematopoietic stem cell transplantation (HSCT) is the standard of care and
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The mutational spectrum of PTPN11 in Juvenile Myelomonocytic Leukemia
2016Co-Authors: Noonan Syndrome/myeloproliferative Disease, Charlotte M. Niemeyer, Henrik Hasle, Peter D. Emanuel, Robert P. Castleberry, Mualla Cetin, Christian P Kratz, Gabriela KardosAbstract:mutations in PTPN11 occur in 35 % of pa-tients with de novo, nonsyndromic Juvenile Myelomonocytic Leukemia(JMML).Myelopro-liferative disorders (MPDs), either transient or more fulminant forms, can also occur in infants with NS (NS/MPD). We identified PTPN11 mutations in blood or bone marrow specimens from 77 newly reported patients with JMML (n 69) or NS/MPD (n 8). To-gether with previous reports, we compared the spectrum of PTPN11 mutations in 3 groups: (1) patients with JMML (n 107); (2) patients with NS/MPD (n 19); and (3) pa-tients with NS (n 243). Glu76 was the most commonlyaffectedresidue inJMML(n 45), with the Glu76Lys alteration (n 29) being most frequent. Eight of 19 patients with NS/ MPD carried the Thr73Ile substitution. These data suggest that there is a genotype/pheno-type correlation in the spectrum of PTPN11 mutations found in patients with JMML, NS/ MPD, and NS. This supports the need to characterize the spectrum of hematologic abnormalities in individuals with NS and to better define the impact of the PTPN11 lesion on the disease course in patients with NS
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acute respiratory failure in 3 children with Juvenile Myelomonocytic Leukemia
Journal of Pediatric Hematology Oncology, 2011Co-Authors: Britt Gustafsson, Marit Hellebostad, Marianne Ifversen, Birgitta Sander, Henrik HasleAbstract:BACKGROUND Juvenile Myelomonocytic Leukemia is a rare hematopoietic stem cell disease in children with features of both myelodysplasia and myeloproliferation. Extramedullary involvement has been reported and pulmonary involvement secondary to leukemic infiltration is an initial manifestation, which may result in acute respiratory failure. OBSERVATION We present 3 children with Juvenile Myelomonocytic Leukemia and suspected pulmonary leukemic cell infiltration who all also suffered from respiratory insufficiency. The differential diagnosis included asthma and infections. CONCLUSIONS In each case the patients improved rapidly after initiation of antileukemic treatment including 6-mercaptopurine or cytarabine.
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aberrant dna methylation characterizes Juvenile Myelomonocytic Leukemia with poor outcome
Blood, 2011Co-Authors: Tania Witte, Rainer Claus, Brigitte Strahm, Peter Nöllke, Anna R Poetsch, Manuela Zucknick, Christiane Olkbatz, Inga Sandrock, Henrik HasleAbstract:Aberrant DNA methylation contributes to the malignant phenotype in virtually all types of cancer, including myeloid Leukemia. We hypothesized that CpG island hypermethylation also occurs in Juvenile Myelomonocytic Leukemia (JMML) and investigated whether it is associated with clinical, hematologic, or prognostic features. Based on quantitative measurements of DNA methylation in 127 JMML cases using mass spectrometry (MassARRAY), we identified 4 gene CpG islands with frequent hypermethylation: BMP4 (36% of patients), CALCA (54%), CDKN2B (22%), and RARB (13%). Hypermethylation was significantly associated with poor prognosis: when the methylation data were transformed into prognostic scores using a LASSO Cox regression model, the 5-year overall survival was 0.41 for patients in the top tertile of scores versus 0.72 in the lowest score tertile (P = .002). Among patients given allogeneic hematopoietic stem cell transplantation, the 5-year cumulative incidence of relapse was 0.52 in the highest versus 0.10 in the lowest score tertile (P = .007). In multivariate models, DNA methylation retained prognostic value independently of other clinical risk factors. Longitudinal analyses indicated that some cases acquired a more extensively methylated phenotype at relapse. In conclusion, our data suggest that a high-methylation phenotype characterizes an aggressive biologic variant of JMML and is an important molecular predictor of outcome.
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gene expression based classification as an independent predictor of clinical outcome in Juvenile Myelomonocytic Leukemia
Journal of Clinical Oncology, 2010Co-Authors: Silvia Bresolin, Henrik Hasle, Christian Flotho, Marco Zecca, Luca Trentin, Andrea Zangrando, Laura Sainati, Jan Stary, Barbara De Moerloose, Charlotte M. NiemeyerAbstract:Purpose Juvenile Myelomonocytic Leukemia (JMML) is a rare early childhood myelodysplastic/myeloproliferative disorder characterized by an aggressive clinical course. Age and hemoglobin F percentage at diagnosis have been reported to predict both survival and outcome after hematopoietic stem cell transplantation (HSCT). However, no genetic markers with prognostic relevance have been identified so far. We applied gene expression–based classification to JMML samples in order to identify prognostic categories related to clinical outcome. Patients and Methods Samples of 44 patients with JMML were available for microarray gene expression analysis. A diagnostic classification (DC) model developed for Leukemia and myelodysplastic syndrome classification was used to classify the specimens and identify prognostically relevant categories. Statistical analysis was performed to determine the prognostic value of the classification and the genes identifying prognostic categories were further analyzed through R software....
Aaron D Gitler - One of the best experts on this subject based on the ideXlab platform.
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tie2 cre induced inactivation of a conditional mutant nf1 allele in mouse results in a myeloproliferative disorder that models Juvenile Myelomonocytic Leukemia
Pediatric Research, 2004Co-Authors: Aaron D Gitler, Warren S Pear, Yi Kong, John K Choi, Jonathan A EpsteinAbstract:Tie2-Cre–Induced Inactivation of a Conditional Mutant Nf1 Allele in Mouse Results in a Myeloproliferative Disorder that Models Juvenile Myelomonocytic Leukemia
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tie2 cre induced inactivation of a conditional mutant nf1 allele in mouse results in a myeloproliferative disorder that models Juvenile Myelomonocytic Leukemia
Pediatric Research, 2004Co-Authors: Aaron D Gitler, Warren S Pear, Yi Kong, John K Choi, Yuan Zhu, Jonathan A EpsteinAbstract:Neurofibromatosis type one (NF1) is a common genetic disorder affecting 1:4000 births and is characterized by benign and malignant tumors. Children with NF1 are predisposed to Juvenile Myelomonocytic Leukemia. The Nf1 gene encodes neurofibromin, which can function as a Ras GTPase-activating protein. Neurofibromin deficiency in mice leads to mid-gestation lethality due to cardiovascular defects. We have previously shown that conditional inactivation of Nf1 using Tie2-Cre recapitulates the heart defects seen in Nf1(-/-) embryos. Tie2-Cre transgenic mice express Cre recombinase in all endothelial cells. Here, we show that Tie2-Cre-mediated deletion of Nf1 also leads to excision of Nf1 in the hematopoietic lineage. Surviving mice exhibit a myeloproliferative disorder similar to Juvenile Myelomonocytic Leukemia seen in NF1 patients. These mice provide a useful model to study neurofibromin deficiency in hematopoiesis. Furthermore, defects in Tie2-Cre-expressing progenitors that result in heart and blood defects suggest that related heart and blood disorders in NF1 and other syndromes represent disorders of the hemangioblast.
