Quantitative Proteome Heterogeneity in Myeloproliferative Neoplasm Subtypes and Association withJAK2Mutation Status.
Apart from well-known genetic abnormalities, several studies have reported variations in protein expression in Philadelphia-negative myeloproliferative neoplasm (MPN) patients that could contribute toward their clinical phenotype. In this context, a quantitative mass spectrometry proteomics protocol was used to identify differences in the granulocyte proteome with the goal to characterize the pathogenic role of aberrant protein expression in MPNs. LC/MS-MS (LTQ Orbitrap) coupled to iTRAQ labeling showed significant and quantitative differences in protein content among various MPN subtypes [polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)], and according to the genetic status ofJAK2(JAK2V617Fpresence andJAK2V617Fallele burden). A number of differentially expressed proteins were identified, with the most frequent being members of the RAS GTPase family and oxidative stress regulatory proteins. Subsequent analysis found that calreticulin (CALR), known to be involved in calcium homeostasis and apoptotic signaling, was overexpressed inJAK2V617Fgranulocytes compared withJAK2wild type and independently of theJAK2V617Fallele burden. Finally, it was demonstrated, in a Ba/F3 cell model, that increased calreticulin expression was directly linked toJAK2V617Fand could be regulated by JAK2 kinase inhibitors.Implications:In conclusion, these results reveal proteome alterations in MPN granulocytes depending on the phenotype and genotype of patients, highlighting new oncogenic mechanisms associated withJAK2mutations and overexpression of calreticulin.Mol Cancer Res; 15(7); 852-61. ©2017 AACR.
TheREx Team (Thérapeutique Recombinante Expérimentale), TIMC-IMAG Laboratory, (Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications de Grenoble), Grenoble Alpes University, Grenoble, France. nuriasocoro@gmail.com.
Nuria
N
Socoro-Yuste
Institute for Medical Research, University of Belgrade, Belgrade, Serbia.
Vladan P
VP
Čokić
TheREx Team (Thérapeutique Recombinante Expérimentale), TIMC-IMAG Laboratory, (Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications de Grenoble), Grenoble Alpes University, Grenoble, France.
Julie
J
Mondet
INSERM, UMR1170. Gustave Roussy. Université Paris-Sud., Villejuif, France.
Isabelle
I
Plo
TheREx Team (Thérapeutique Recombinante Expérimentale), TIMC-IMAG Laboratory, (Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications de Grenoble), Grenoble Alpes University, Grenoble, France.|Laboratoire d'Hématologie Cellulaire, Institut de Biologie et Pathologie, Grenoble Alpes University Hospital, Grenoble, France.
Pascal
P
Mossuz
D037282:Calreticulin / Q000235:genetics*; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018740:Genetic Heterogeneity; D005838:Genotype; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D009154:Mutation; D011087:Polycythemia Vera / Q000097:blood / Q000235:genetics* / Q000473:pathology; D055728:Primary Myelofibrosis / Q000097:blood / Q000235:genetics* / Q000473:pathology; D020543:Proteome / Q000235:genetics; D013920:Thrombocythemia, Essential / Q000097:blood / Q000235:genetics* / Q000473:pathology
D037282:Calreticulin; D020543:Proteome; C507924:JAK2 protein, human; D053614:Janus Kinase 2