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Proteomic Analysis of an Induced Pluripotent Stem Cell Model Reveals Strategies to Treat Juvenile Myelomonocytic Leukemia
- Source :
- Journal of Proteome Research
- Publication Year :
- 2019
- Publisher :
- American Chemical Society, 2019.
-
Abstract
- 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 an increased incidence of JMML. We report that the proteomic perturbations induced by the leukemia-associated PTPN11 mutations are associated with TP53 and NF-Kκb signaling. We have previously shown that MYC is involved in the differential gene expression observed in Noonan syndrome patients associated with an increased incidence of JMML. Thus, we employed drugs to target these pathways and demonstrate differential effects on clonogenic hematopoietic cells derived from Noonan syndrome patients, who develop JMML and those who do not. Further, we demonstrated these small molecular inhibitors, JQ1 and CBL0137, preferentially extinguish primitive hematopoietic cells from sporadic JMML patients as opposed to cells from healthy individuals.
- Subjects :
- 0301 basic medicine
musculoskeletal diseases
Proteomics
congenital, hereditary, and neonatal diseases and abnormalities
curaxin
Induced Pluripotent Stem Cells
PTPN11
Biochemistry
Article
03 medical and health sciences
Germline mutation
medicine
Humans
Clonogenic assay
Induced pluripotent stem cell
skin and connective tissue diseases
Child
Myeloproliferative neoplasm
030102 biochemistry & molecular biology
Juvenile myelomonocytic leukemia
business.industry
Noonan Syndrome
General Chemistry
medicine.disease
Haematopoiesis
CBL0137
030104 developmental biology
Leukemia, Myelomonocytic, Juvenile
Child, Preschool
Mutation
Cancer research
Noonan syndrome
business
Subjects
Details
- Language :
- English
- ISSN :
- 15353907 and 15353893
- Volume :
- 19
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of Proteome Research
- Accession number :
- edsair.doi.dedup.....370fc3a94983055c79af0659d065fc86