Cell type-specific apoptosis resistance in juvenile myelomonocytic leukemia
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE277667 | GEO | 2025/03/19
REPOSITORIES: GEO
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Project description:Sepsis induces lymphocyte apoptosis which can be prevented by over-expression of anti-apoptotic Bcl-2 family members. The anti-apoptotic activity of Bcl-2 family members is localized in the BH4 domain. The therapeutic peptide, TAT-BH4, was found to prevent sepsis-induced lymphocyte apoptosis in vivo. We also showed that this peptide prevents PBMC apoptosis in response to bacterial exudate. Here we studied whether there was a transcriptional component to that protection in vitro in bacterially-induced PBMC apoptosis.
2006-02-07 | E-MEXP-555 | biostudies-arrayexpress
Project description:Juvenile myelomonocytic leukemia (JMML) is an aggressive hematologic malignancy with myeloproliferative characteristics that affects young children and is associated with significant morbidity and mortality. Leukemia stem cells (LSCs) have been shown to drive relapse and progression in JMML and include Lin-CD34+CD38-/+ hematopoietic stem cells (HSCs)14. We therefore sought to develop cellular immunotherapy against JMML by employing a multi-modal omics strategy, focusing specifically on targeting chemoresistant LSCs
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Project description:Targeting BET bromodomain proteins utilizing small molecules in an emerging anti-cancer strategy with clinical evaluation of at least six inhibitors now underway. While MYC downregulation was initially proposed as a key mechanistic property of BET inhibitors, recent evidence suggests that additional anti-tumor activities are important. Using the Eμ-Myc model of B-cell lymphoma we demonstrate that BET inhibition with JQ1 is a potent inducer of p53-independent apoptosis that occurs in the absence of effects on Myc gene expression. JQ1 skews the expression of pro-apoptotic (Bim) and anti-apoptotic (BCL-2/BCL-xL) BCL-2 family members to directly engage the mitochondrial apoptotic pathway. Consistent with this, Bim knockout or Bcl-2 overexpression inhibited apoptosis induction by JQ1. We identified lymphomas that were either intrinsically resistant to JQ1-mediated death or acquired resistance following in vivo exposure. Strikingly, in both instances BCL-2 was strongly upregulated and was concomitant with activation of RAS pathways. Eμ-Myc lymphomas engineered to express activated Nras upregulated BCL-2 and acquired a JQ1-resistance phenotype. These studies provide important information on mechanisms apoptosis induction and resistance to BET-inhibition, while providing further rationale for the translation of BET inhibitors in aggressive B-cell lymphomas.
2016-09-18 | GSE87050 | GEO
Project description:Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of early childhood with a poor survival rate thus there is a requirement for improved treatment strategies. Induced pluripotent stem cells offer the ability to model disease and develop new treatment strategies. JMML is frequently associated with mutations in PTPN11. Children with Noonan syndrome, a development disorder, have an increased incidence of JMML associated with specific germline mutations in PTPN11. We undertook a proteomic assessment of myeloid cells derived from induced pluripotent stem cells obtained from Noonan syndrome patients with PTPN11 mutations, either associated or not associated with increased incidence of JMML. We report that the proteomic perturbations induced by the leukaemia-associated PTPN11 mutations are associated with TP53 and NF-ĸb signalling. We have previously shown that MYC is involved in the differential gene expression observed in Noonan syndrome patients associated with increased incidence of JMML. Thus, we employed drugs to target these pathways and demonstrate differentential effects on clonogenic hematopoietic cells derived from Noonan syndrome patients whom develop JMML and those who do not. Further, we demonstrated these small molecular inhibitors, JQ1 and CBL0137, preferentially extinguish primitive haematopoietic cells from sporadic JMML patients as opposed to cells from healthy individuals.
2019-10-30 | PXD014708 | Pride
Project description:Juvenile myelomonocytic leukemia (JMML) is a very rare and aggressive stem cell disease that mainly occurs in young children. RAS activation constitutes the core component of oncogenic signaling. In addition, the leukemic blasts of a quarter of JMML patients present with monosomy 7 (-7), whereas more than half of the patients show enhanced age-adjusted fetal hemoglobin (HbF) levels. Hematopoietic stem cell transplantation is the current standard of care. This results in an event-free survival of 50 - 60%, indicating that novel molecular driven therapeutic options are urgently needed. Using gene expression profiling in an extensive series of 82 patient samples, we aimed at understanding the molecular biology behind JMML and identified a previously unrecognized molecular subgroup characterized by high LIN28B expression. Interestingly, LIN28B overexpression was significantly correlated with higher HbF levels whereas patients with -7 seldom showed enhanced LIN28B expression. In line with LIN28Bâ??s role as mediator of fetal hematopoiesis, this explains the biology behind the observation that patients with -7 are rarely diagnosed with high age-adjusted HbF levels. In addition, this new fetal-like JMML subgroup presented with reduced levels of most members of the let-7 microRNA family and showed characteristic overexpression of genes involved in fetal hematopoiesis and stem cell self-renewal. Finally, high LIN28B expression was associated with poor clinical outcome in our JMML patient series, but not independent from other prognostic factors such as age and age-adjusted HbF levels. In conclusion, we identified LIN28B as a crucial molecular player at the heart of a novel fetal-like subgroup in JMML. Gene expression was measured on Affymetrix in 38 JMML patients and 9 healthy donors in a validation cohort.
2015-12-23 | E-GEOD-71935 | biostudies-arrayexpress
Project description:Juvenile myelomonocytic leukemia (JMML) is an aggressive cancer of young children initiated by mutations in NRAS, KRAS and other genes encoding proteins that modulate Ras signal output. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment and patients with relapsed and refractory disease have dismal outcomes. This trial evaluated the safety and efficacy of trametinib in advanced JMML. Kinase enrichment proteomic analysis was performed using available patient samples pre- or post-treatment with trametinib (NCT03190915) to evaluate the effects on the functional kinome.
2024-04-23 | PXD042328 | Pride
Project description:Juvenile myelomonocytic leukemia (JMML) is a very rare and aggressive stem cell disease that mainly occurs in young children. RAS activation constitutes the core component of oncogenic signaling. In addition, the leukemic blasts of a quarter of JMML patients present with monosomy 7 (-7), whereas more than half of the patients show enhanced age-adjusted fetal hemoglobin (HbF) levels. Hematopoietic stem cell transplantation is the current standard of care. This results in an event-free survival of 50 - 60%, indicating that novel molecular driven therapeutic options are urgently needed. Using gene expression profiling in an extensive series of 82 patient samples, we aimed at understanding the molecular biology behind JMML and identified a previously unrecognized molecular subgroup characterized by high LIN28B expression. Interestingly, LIN28B overexpression was significantly correlated with higher HbF levels whereas patients with -7 seldom showed enhanced LIN28B expression. In line with LIN28Bâ??s role as mediator of fetal hematopoiesis, this explains the biology behind the observation that patients with -7 are rarely diagnosed with high age-adjusted HbF levels. In addition, this new fetal-like JMML subgroup presented with reduced levels of most members of the let-7 microRNA family and showed characteristic overexpression of genes involved in fetal hematopoiesis and stem cell self-renewal. Finally, high LIN28B expression was associated with poor clinical outcome in our JMML patient series, but not independent from other prognostic factors such as age and age-adjusted HbF levels. In conclusion, we identified LIN28B as a crucial molecular player at the heart of a novel fetal-like subgroup in JMML. Gene expression was measured on Agilent in 44 JMML patients and 7 healthy donors in the discovery cohort. A validation cohort of 38 patients and 9 healthy donors was measured on Affymetrix. All patient data can be found in Supplementary Table S1.
2015-12-23 | E-GEOD-71449 | biostudies-arrayexpress
Project description:Juvenile myelomonocytic leukemia (JMML), a clonal hematologic malignancy, originates from mutated hematopoietic stem cells (HSCs) with genetic alterations in the Ras signaling pathway. The mechanism sustaining the persistence of these mutant stem cells leading to leukemia development remains poorly understood. In this study, we conducted comprehensive examination of gene expression profiles, transcriptional factor regulones, and cell compositions throughout various stages of tumor cell development in a mouse model of Ptpn11 mutation-associated JMML. Our analyses unveiled that leukemia-initiating Ptpn11E76K/+ mutant stem cells exhibited de novo activation of the myeloid transcriptional program and aberrant developmental trajectories. Intriguingly, these mutant stem cells displayed significantly elevated expression levels of anti-microbial molecules and pro-inflammatory proteins, particularly S100a9 and S100a8. These proteins conferred a selective advantage to leukemia-initiating cells through autocrine effects and facilitated immune evasion by recruiting and promoting immune suppressive myeloid-derived suppressor cells (MDSCs) to the microenvironment. Importantly, pharmacological inhibition of S100a9/S100a8 signaling effectively impeded leukemia development from Ptpn11E76K/+ mutant stem cells. These findings collectively suggest that JMML tumor-initiating cells exploit evolutionarily conserved innate immune and inflammatory mechanism to establish clonal dominance.
2024-09-12 | GSE266821 | GEO
Project description:Juvenile myelomonocytic leukemia (JMML) is a very rare and aggressive stem cell disease that mainly occurs in young children. RAS activation constitutes the core component of oncogenic signaling. In addition, the leukemic blasts of a quarter of JMML patients present with monosomy 7 (-7), whereas more than half of the patients show enhanced age-adjusted fetal hemoglobin (HbF) levels. Hematopoietic stem cell transplantation is the current standard of care. This results in an event-free survival of 50 - 60%, indicating that novel molecular driven therapeutic options are urgently needed. Using gene expression profiling in an extensive series of 82 patient samples, we aimed at understanding the molecular biology behind JMML and identified a previously unrecognized molecular subgroup characterized by high LIN28B expression. Interestingly, LIN28B overexpression was significantly correlated with higher HbF levels whereas patients with -7 seldom showed enhanced LIN28B expression. In line with LIN28B’s role as mediator of fetal hematopoiesis, this explains the biology behind the observation that patients with -7 are rarely diagnosed with high age-adjusted HbF levels. In addition, this new fetal-like JMML subgroup presented with reduced levels of most members of the let-7 microRNA family and showed characteristic overexpression of genes involved in fetal hematopoiesis and stem cell self-renewal. Finally, high LIN28B expression was associated with poor clinical outcome in our JMML patient series, but not independent from other prognostic factors such as age and age-adjusted HbF levels. In conclusion, we identified LIN28B as a crucial molecular player at the heart of a novel fetal-like subgroup in JMML.
2015-12-23 | GSE71452 | GEO
Project description:Juvenile myelomonocytic leukemia (JMML) is a very rare and aggressive stem cell disease that mainly occurs in young children. RAS activation constitutes the core component of oncogenic signaling. In addition, the leukemic blasts of a quarter of JMML patients present with monosomy 7 (-7), whereas more than half of the patients show enhanced age-adjusted fetal hemoglobin (HbF) levels. Hematopoietic stem cell transplantation is the current standard of care. This results in an event-free survival of 50 - 60%, indicating that novel molecular driven therapeutic options are urgently needed. Using gene expression profiling in an extensive series of 82 patient samples, we aimed at understanding the molecular biology behind JMML and identified a previously unrecognized molecular subgroup characterized by high LIN28B expression. Interestingly, LIN28B overexpression was significantly correlated with higher HbF levels whereas patients with -7 seldom showed enhanced LIN28B expression. In line with LIN28B’s role as mediator of fetal hematopoiesis, this explains the biology behind the observation that patients with -7 are rarely diagnosed with high age-adjusted HbF levels. In addition, this new fetal-like JMML subgroup presented with reduced levels of most members of the let-7 microRNA family and showed characteristic overexpression of genes involved in fetal hematopoiesis and stem cell self-renewal. Finally, high LIN28B expression was associated with poor clinical outcome in our JMML patient series, but not independent from other prognostic factors such as age and age-adjusted HbF levels. In conclusion, we identified LIN28B as a crucial molecular player at the heart of a novel fetal-like subgroup in JMML.
2015-12-23 | GSE71449 | GEO