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Gene exprssion profile classification predicts clinical outcome in juvenile myelomonocytic leukemia

ABSTRACT: Gene expression analysis identified a specific signature of differentially expressed genes discriminating good and poor responders in JMML patients. Gene expression signatures were analyzed on two EWOG patient cohorts of pediatric JMML patients. Keywords: Expression data

ORGANISM(S): Homo sapiens

PROVIDER: GSE14858 | GEO | 2010/01/01

SECONDARY ACCESSION(S): PRJNA112143

REPOSITORIES: GEO

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Gene exprssion profile classification predicts clinical outcome in juvenile myelomonocytic leukemia

Project description:Gene expression analysis identified a specific signature of differentially expressed genes discriminating good and poor responders in JMML patients. Gene expression signatures were analyzed on two EWOG patient cohorts of pediatric JMML patients. Keywords: Expression data Class comparison between AML-like vs non-AML-like signatures in JMML patients.

2009-12-31 | E-GEOD-14858 | biostudies-arrayexpress

Proteomic analysis of an induced pluripotent stem cell model reveals strategies to treat Juvenile Myelomonocytic Leukaemia

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.

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Total paired-end RNA sequencing of bone marrow and peripheral blood MNCs from patients with Juvenile myelomonocytic leukemia and age-matched controls

Project description:Dysregulation of the non-coding RNA transcriptome has been demonstrated in Juvenile myelomonocytic leukemia (JMML), a rare and aggressive disorder of early childhood. Currently, JMML treatment relies on hematopoietic stem cell transplantation resulting in long-term overall survival of only 50-60%. Consequently, there is need to develop novel treatments. In this study we investigated the therapeutic potential of targeting overexpressed long non-coding RNAs (lncRNAs) in JMML. Total RNA sequencing from 19 previously untreated JMML patients and 3 pediatric normal bone marrow samples revealed 202 differentially expressed lncRNA genes (144 upregulated and 58 downregulated). Molecular knockdown (≥ 70% compared to mock control) after 24h of incubation was observed for 6 out of 10 overexpressed lncRNAs for which LNA GapmeRs were designed. For 3 lncRNAs (lnc-THADA-4-1, lnc-ACOT9-1 and NRIR) knockdown resulted in a significant effect on cell viability after 96h or 72h of incubation in cell lines or in primary JMML cells, respectively. Importantly, the extend of cellular damage correlated well with the expression of the lncRNA of interest. In conclusion, we provided proof-of-concept that knockdown of overexpressed lncRNAs such as lnc-THADA-4-1, lnc-ACOT9-1 and NRIR is a feasible therapeutic strategy in vitro in haematopoietic cell lines and in primary JMML cells. These results will need further validation in JMML xenograft models.

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Exomes of human leukemic JMML (Juvenile MyeloMonocytic Leukemia) xenografts in NSG or NSG-S mice (samples enriched in hCD45)

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Genome-wide DNA Methylation is Predictive of Outcome in Juvenile Myelomonocytic Leukemia

Project description:Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder of childhood caused by mutations in the Ras pathway. Outcomes in this disease vary dramatically from spontaneous resolution with little or no treatment to rapid relapse after hematopoietic stem cell transplantation. Given the high morbidity and late effects of transplant, it is critical to identify patients at diagnosis who can be observed rather than transplanted. We hypothesized that assessing DNA methylation status would help predict disease outcome. Genome-wide DNA methylation profiling using the Illumina 450k platform in a discovery cohort of 39 patients was performed. Unsupervised hierarchical clustering based on the most highly variable CpG sites identified three clusters of patients. Importantly, these clusters differed 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. Of particular interest is that all but one of fourteen patients experiencing spontaneous resolution of their disease clustered together and closer to 22 healthy controls than the other JMML cases. This study demonstrates that DNA methylation patterns in JMML are predictive of outcome in this heterogeneously behaving disease and can identify patients who are most likely to experience spontaneous resolution.

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Genomic and epigenomic characterization of juvenile myelomonocytic leukemia (JMML)

Project description:Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood. While some cases show spontaneous remission, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment option for the majority of patients, however, the 5-year event-free survival reaches only about 50%. Hyperactive RAS signaling is assumed to be the main driving event in JMML. It is caused by genetic alterations in CBL, KRAS, NF1, NRAS, or PTPN11 in about 90% of patients. So far, there is no clear understanding of how RAS pathway mutations relate to the heterogeneous disease biology and variable clinical outcome seen in JMML patients. As a consequence, established clinical and genetic markers fail to fully represent the observed disease heterogeneity. We hypothesized that DNA methylation profiling, either alone or in combination with genetic alterations, might provide a molecular basis for disease classification. Genome wide DNA methylation analysis using the HumanMethylation450 Bead Chip array was performed in a discovery cohort of 20 patients (19 JMML, 1 Noonan syndrome). The clinical relevance of our findings was assessed in an unselected sample set consisting of 147 consecutive patients with JMML (n=129) or Noonan syndrome (n=18) associated myeloproliferative disorder (n=18) registered in the EWOG-MDS 1998 & 2006 trials. Data integration was performed in a subset of patients with available exome sequencing (n=50) and expression profiling (n=15) data. This integrated approach identified three JMML subgroups characterized by distinct clinical and biological features. This analysis further suggested a molecular mechanism by which additional genetic events, presumably further activating the RAS-RAF-MEK-ERK pathway, mediate DNA hypermethylation via up-regulation of DNMTs in more aggressive JMML cases.

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Prototypical innate immune mechanism hijacked by leukemia-initiating mutant stem cells for selective advantage and immune evasion in Ptpn11 mutation-associated juvenile myelomonocytic leukemia

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.

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