Circulating CD133+/–CD34– Have Increased c-MYC Expression in Myeloproliferative Neoplasms

Abstract

Objective: Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell (HSC)-originated diseases with clonal myeloproliferation. The constitutive activation of the JAK/STAT pathway is frequently detected in patients with Philadelphia chromosome-negative (Ph – ) MPNs with an acquired JAK2 V617F mutation. The c- MYC proto-oncogene is associated with malignant growth and cellular transformation, and JAK2 V617F was previously shown to induce constitutive expression of c- MYC . This study examines the expressional profile of c- MYC in Ph – MPNs with JAK2 V617F and highlights its hierarchical level of activation in circulating hematopoietic stem/progenitor cell (HSPC) subgroups. Materials and Methods: Mononuclear cells (MNCs) of Ph – MPNs were fluorochrome-labeled in situ with wild-type (wt) JAK2 or JAK2 V617F mRNA gold nanoparticle technology and sorted simultaneously. Isolated populations of JAK2 wt or JAK2 V617F were evaluated for their c- MYC expressions. The MNCs of 14 Ph – MPNs were further isolated for the study of HSPC subgroups regarding their CD34 and CD133 expressions, evaluated for the presence of JAK2 V617F, and compared to cord blood (CB) counterparts for the expression of c- MYC . Results: The mRNA-labeled gold nanoparticle-treated MNCs were determined to have the highest ratio of c- MYC relative fold-change expression in the biallelic JAK2 V617F compartment compared to JAK2 wt. The relative c- MYC expression in MNCs of MPNs was significantly increased compared to CB (p=0.01). The circulating HSPCs of CD133 +/– CD34 − MPNs had statistically significantly elevated c- MYC expression compared to CB. Conclusion: This is the first study of circulating CD133 +/– CD34 − cells in Ph – MPNs and it has revealed elevated c- MYC expression levels in HSCs/endothelial progenitor cells (HSCs/EPCs) and EPCs. Furthermore, the steady increase in the expression of c- MYC within MNCs carrying no mutations and monoallelic or biallelic JAK2 V617F transcripts was notable. The presence of JAK2 V617F with respect to c- MYC expression in the circulating HSCs/EPCs and EPCs of ...

Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms

“…In addition, c-Myc suppresses GADD45g gene expression in prostate cancer cells 37 , 38 . Notably, JAK2V617F mutation is reported to induce the activation of NF-κB and STAT3 3 , 39 , as well as constitutive expression of c-Myc 40 in MPNs. Therefore, activations of NF-κB, STAT3 and c-Myc, either singly or in combination, might contribute to the downregulation of GADD45g by JAK2V617F mutation in MPNs, which warrants further study.…”