Long-term proliferation of immature hypoxia-dependent JMML cells supported by a 3D in vitro system
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ABSTRACT:
PROVIDER: PRJNA779629 | ENA |
REPOSITORIES: ENA
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Project description:Juvenile myelomonocytic leukemia (JMML) is a rare stem cell disorder occurring in early childhood and characterized by RAS pathway hyperactivation in 95% of patients. JMML is identified by a hyperproliferation of granulocyte and monocyte, and little is known about the heterogeneous nature of leukemia initiating cells as well as the cellular hierarchy of the JMML bone marrow (BM). In this study, we reported the generation and characterization of a novel patient-derived 3D in vitro JMML model (pd-JAO) sustaining long-term proliferation of JMML cells with stem cell features and patient specific hallmarks. JMML cells brewed in the 3D model under different microenvironmental conditions acquired a proliferative and survival advantage when placed at low oxygen tensions. Transcriptomic and microscopic analysis revealed the activation of specific metabolic energy pathways and the inactivation of processes leading to cell death. Furthermore, we demonstrated pd-JAO derived cells’ migratory, propagation and self-renewal capacities both in in vitro and in vivo mouse model. Our study contributed to the development of a robust JMML 3D in vitro model to study and comprehend the impact of microenvironment stimuli on JMML disease and the molecular mechanisms regulating JMML initiating and propagating cells. Pd-JAO may become a promising model for compound tests focusing on new therapeutic intervention aiming to eradicate JMML progenitors and control JMML disease. We defined a 3D in vitro model that under hypoxic conditions is able to sustain long-term propagation of JMML-patients cells with specific hallmarks. Different oxygen level enviroment drive specific metabolic switch that prompts JMML cells to self-renewal.
2023-04-03 | GSE188608 | GEO
Project description:Juvenile myelomonocytic leukemia (JMML) is a rare clonal stem cell disorder that occurs in early childhood and is characterized by the hyperactivation of the RAS pathway in 95% of the patients. JMML is characterized by a hyperproliferation of granulocytes and monocytes, and little is known about the heterogeneous nature of leukemia-initiating cells, as well as of the cellular hierarchy of the JMML bone marrow. In this study, we report the generation and characterization of a novel patient-derived three-dimensional (3D) in vitro JMML model, called patient-derived JMML Atypical Organoid (pd-JAO), sustaining the long-term proliferation of JMML cells with stem cell features and patient-specific hallmarks. JMML cells brewed in a 3D model under different microenvironmental conditions acquired proliferative and survival advantages when placed under low oxygen tension. Transcriptomic and microscopic analyses revealed the activation of specific metabolic energy pathways and the inactivation of processes leading to cell death. Furthermore, we demonstrated the pd-JAO-derived cells' migratory, propagation, and self-renewal capacities. Our study contributes to the development of a robust JMML 3D in vitro model for studying and defining the impact of microenvironmental stimuli on JMML disease and the molecular mechanisms that regulate JMML initiating and propagating cells. Pd-JAO may become a promising model for compound tests focusing on new therapeutic interventions aimed at eradicating JMML progenitors and controlling JMML disease.
| S-EPMC10130612 | biostudies-literature
Project description:Activating mutations in PTPN11 gene are the most frequent in JMML patients. Here we explore the transcriptome of HSPC (hematopoietic stem and progenitor cells) sorted from sporadic JMML patients with PTPN11 mutation and from healthy age matched donnors. Bulk transcriptome of sorted HSPC reveals an inflammatory gene expression signature which may represent a future target for JMML therapy.
2021-09-06 | GSE183252 | GEO
Project description:JMML (Juvenile myelomonocytic leukaemia) is a leukaemia hat only develops in young children and is thought to have a prenatal initiation. To study the relationship between JMML and normal ontogeny we studied the transcriptome of HSPC (hematopoietic stem and progenitor cells) sorted from sporadic JMML patients, healthy prenatal samples and from healthy age matched donors. Bulk transcriptome of sorted HSPC reveals that some JMML samples cluster with prenatal samples whereas other from a distinct cluster apart from any healthy samples. Methylation profile on bulk mononucleated cell on theses JMML patients, 2 healthy postnatal and 2 healthy prenatal samples is also investigated. The results show a global hypermethylation in JMML samples compared to healthy samples and a specific JMML group with a hypermethylated profile compared to all JMML samples.
2022-12-31 | GSE198919 | GEO
Project description:JMML (Juvenile myelomonocytic leukaemia) is a leukaemia that only develops in young children and is thought to have a prenatal initiation. To study the relationship between JMML and normal ontogeny we studied the transcriptome of HPC (hematopoietic progenitor cells) sorted from sporadic JMML patients, healthy prenatal samples and from healthy age matched donors. Bulk transcriptome of sorted HPC reveals that some JMML samples cluster with prenatal samples whereas other from a distinct cluster apart from any healthy samples.
2024-05-16 | GSE267628 | GEO
Project description:Individual drug treatment in a mouse model of JMML equally ameliorates monocytosis and splenomegaly but combined treatment uniquely ameliorates thrombocytopenia.
2021-10-11 | GSE185552 | 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
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 | GSE71935 | GEO
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