The Novel Functions of JAK2 in the treatment of MPD

JAK2 Inhibitor Induction of Apoptosis and Cell-Cycle Arrest in Human Erythroleukemic Cancer Cells

Hillel Friedman

Hebrew Academy of the Five Towns and Rockaway

Cedarhurst, New York�

Abstract

The genotypical hallmark of many myeloproliferative disorders (MPD), cacners characterized by excessive blood production in the bone marrow, is the JAK2V617F mutation. This project tested JAK2 inhibitors' ability to precisely target these malignancies, investigating their role in the p53-mediated apoptosis and cell-cycle arrest responses on JAK2V617F+ HEL cells to evaluate their therapeutic potential for MPD patients. Additionally, since autophagy may be critical in reducing tumor formation and metastasis in MPD patients, the JAK2 inhibitor's effect was tested on Damage Regulated Autophagy Modulator (DRAM), a protein which induces cellular degradation.

HEL cells were treated with JAK inhibitor 1 at 0hr, 2hr, and 16hr timepoints. Initially, a western blot of JAK2 was performed to ensure inhibition of JAK2 post-treatment. Following confirmation, apoptosis and cell-cycle assays, qPCR analysis of p53 and DRAM and an autophagy level assay were performed to determine the effects of the inhibition of JAK2 on cellular responses.

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Results indicate, for the first time, that inhibition of JAK2 upregulates p53 and DRAM, constituting augmented apoptosis, cell-cycle arrest and autophagy, suggesting that JAK2 inhibitors can reduce cancerous cell proliferation via the named mechanisms and promising a new therapeutic approach in the battle against MPD.

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Overview

In 2002, my father was diagnosed with non-Hodgkin's lymphoma and was treated with a drug that had promises of success. In 2006, however, the tables turned as the very drug that intended to cure him gave him acute myelogenous leukemia (AML), a cancer which ranks as one of the top five most fatal. Thankfully, he survived; but this experience allowed me to witness firsthand the risks and complications of current treatment options. Motivated by these events, I investigated...