TY - JOUR

T1 - Proteomic analysis of an induced pluripotent stem cell model reveals strategies to treat Juvenile Myelomonocytic Leukaemia

AU - Pearson, Stella

AU - Guo, Baoqiang

AU - Pierce, Andrew

AU - Azadbakht, Narges

AU - Brazzatti, Julie A.

AU - Patassini, Stefano

AU - Mulero-navarro, Sonia

AU - Meyer, Stefan

AU - Flotho, Christian

AU - Gelb, Bruce D.

AU - Whetton, Anthony D.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - Juvenile myelomonocytic leukemia

KW - curaxin

KW - Induced pluripotent stem cells

KW - PTPN11

KW - CBL0137

U2 - 10.1021/acs.jproteome.9b00495

DO - 10.1021/acs.jproteome.9b00495

M3 - Article

JO - Journal of Proteome Research

JF - Journal of Proteome Research

SN - 1535-3893

ER -