Gabriela Lezama Martinez
Research Mentor(s): Malathi Kandarpa
Department or Program: Internal Med- Hematology/Oncology
Authors: Gabriela Lezama Martinez, Mary Nguyen, Malathi Kandarpa, PhD.
Session: Session 1: 12:00pm-12:50pm
Poster: 25
Abstract
Myeloproliferative neoplasms (MPN), comprising of essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), are a group of hematological malignancies characterized by the hyperproliferation of hematopoietic stem cells. These blood cancers share driver mutations in JAK2, MPL, or CALR genes that lead to the constitutive activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, which is involved in processes such as cell growth and proliferation, hematopoiesis, and cytokine production. Ruxolitinib and fedratinib are both JAK inhibitors that disrupt the phosphorylation of JAK2, thereby preventing subsequent phosphorylation of STAT proteins and interfering with downstream signaling pathways. While both drugs hold potential for reducing abnormal cell proliferation in patients with myeloproliferative neoplasms, ruxolitinib is currently more widely used in clinical settings compared to the more recent drug fedratinib, which has shown broader activity and disease reversal. This study aims to compare the effectiveness of ruxolitinib and fedratinib in inhibiting JAK2 activity, thus providing insight into the most effective treatment option for MPN patients. The hypotheses we are testing are: 1) mutant MPL and JAK2 expressing cells are more sensitive to JAK2 inhibitors, and 2) fedratinib has broader activity in these cell line models. Sensitivity to drugs was measured by MTT assay in human erythroleukemia cell lines, TF1 (WT), and TF1 expressing MPLW515L. The effect of these drugs on inhibiting activation of the JAK/STAT pathway will be further evaluated for phospho-STAT3 and phospho-STAT5 by immunoblotting. Preliminary cell survival measurements suggest that TF1 cells expressing MPLW515L are sensitive to both ruxolitinib and fedratinib. Differential sensitivity of MPLW515L and JAK2V617F expressing TF1 cells is currently being studied. Differential activation of STAT pathway and other downstream effects will also be interrogated in cell line models with the goal of determining the signaling pathways that distinguish the drug activity. These results will elucidate the differential activity of JAK2 inhibitors to establish the best regimen that holds promise in improving outcomes in MPN patients.
