Proteomic Analysis of an Induced Pluripotent Stem Cell Model Reveals Strategies to Treat Juvenile Myelomonocytic Leukemia

Stella Pearson, Baoqiang Guo, Andrew Pierce, Narges Azadbakht, Julie A. Brazzatti, Stefano Patassini, Sonia Mulero-Navarro, Stefan Meyer, Christian Flotho, Bruce D. Gelb, Anthony D. Whetton

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish
Pages (from-to)194-203
Number of pages10
JournalJournal of Proteome Research
Volume19
Issue number1
DOIs
StatePublished - 3 Jan 2020

Keywords

  • CBL0137
  • Induced pluripotent stem cells
  • Juvenile myelomonocytic leukemia
  • PTPN11
  • curaxin

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