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Sustained fetal hematopoiesis causes juvenile death from leukemia: evidence from a dual-age-specific mouse model

ABSTRACT: It is not clear whether disrupted age-specific hematopoiesis contributes to the complex manifestations in leukemia patients who carry identical mutations, particularly in pediatric and adult patients with similar clinical characteristics. By studying a dual-age-specific mouse model, we demonstrate: 1) loss of Pten during the fetal-to-adult hematopoiesis switch (HSC switch) causes sustained fetal hematopoiesis, resulting in death in juvenile leukemia; 2) myeloid-biased hematopoiesis in juvenile mice is associated with the sustained fetal properties of hematopoietic stem cells (HSCs); 3) the age specificity of juvenile myelomonocytic leukemia (JMML) depends on the dosage of Pten and Nf1; 4) single-allelic Pten deletion during the HSC switch causes constitutive activation of mitogen-activated protein kinase (MAPK) in juvenile mice with Nf1 loss of heterozygosity (LOH); and 5) Nf1 LOH causes monocytosis in juvenile mice with Pten haploinsufficiency but does not cause lethality until adulthood. Our data suggest that one copy of Pten is sufficient to maintain an intact negative feedback loop of the Akt pathway and HSC function in reconstitution, despite MAPK being constitutively activated in juvenile mice with Pten+/DNf1LOH. However, two copies of Pten are required to maintain the integrity of the MAPK pathway in juvenile mice with Nf1 haploinsufficiency. Our data indicate that previous investigations of Pten function in wild type mice may not reflect the impact of Pten loss in mice with Nf1 mutations or other genetic defects. We provide a proof-of-concept that disassociated age-specific hematopoiesis contributes to leukemogenesis and pediatric demise.

ORGANISM(S): Mus musculus

PROVIDER: GSE137152 | GEO | 2020/06/25

REPOSITORIES: GEO

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Project description:Background: Signaling by receptor tyrosine kinases (RTK) is frequently dysregulated in gliomas. Inter-individual variability in the causes for dysregulated RTK signaling may have hampered the efficacy of targeted therapies. Using gene expression modules around key regulators in the RAS-RAF-MEK-MAPK cascade and in the phosphatidylinositol 3-kinase-AKT pathways, we developed a âRMPAâ clustering scheme to distinguish gliomas with varying extents of RTK signaling. Results: We identified gene modules consistently co-expressed with NF1 (NF1-M), Sprouty (SPRY-M) and PTEN (PTEN-M) in gliomas. Their signatures enabled robust clustering of adult diffuse gliomas of WHO grades II-IV into RMPAhigh and RMPAlow phenotypes in a morphology-independent manner. In five independent data sets from three continents containing more than 1500 adult diffuse gliomas, RMPAhigh gliomas were associated with poor prognosis while RMPAlow gliomas were not. The RMPAhigh and RMPAlow glioma subtypes showed distinct levels of the activities of RAS-RAF-MEK-MAPK cascade and PI3K-AKT pathway and harbored unique sets of genomic alterations in the RTK signaling-related genes. The RMPAhigh gliomas contained large numbers of immature vessel cells and tumor associated macrophages and both cell types expressed high levels of pro-angiogenic RTKs including MET, VEGFR1, KDR, EPHB4 and NRP1. Conclusion: Inter-glioma variability in RTK signaling activities can be defined using the RMPA clustering scheme. The combined signatures of NF1-M, SPRY-M and PTEN-M reflect RTK signaling activity both in the glioma cells and in the glioma microenvironment. Our data show that RTK signaling in the glioma microenvironment may play a pivotal role in glioma progression. Transcriptome data from 22 fresh gliomas (2 astrocytoma II, 1 oligodendrocytoma II, 7 oligoastrocytoma II, 4 anaplastic oligoastrocytoma III and 8 GBM) were obtained using Affymetrix Human Gene 1.0 ST Array. Unsupervised hierarchical clustering of the expression data for the SPRY-M, NF1-M and PTEN-M was performed on these transcriptome data to identify samples with RMPAhigh or RMPAlow signature.

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Sustained fetal hematopoiesis causes juvenile death from leukemia: evidence from a dual-age-specific mouse model

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