Characterizing and targeting the JAK/STAT pathway in LGL leukemia 478 views

LGL leukemia is a rare hematological malignancy that typically runs an indolent course, but all patients eventually require treatment. LGL leukemia encompasses three subtypes; T-cell, chronic NK-cell and aggressive NK-LGL leukemia. Current LGL leukemia therapy includes utilization of broad immunosuppressants including Methotrexate, Cyclophosphamide and Cytoxan. While these drugs show efficacy in reducing symptoms, none of them are curative, and may cause adverse effects and higher susceptibility to infections. A central goal of the Loughran lab is to identify better therapeutics for LGL leukemia. Genomic analysis of cancer offers the hope of identifying new treatments or aiding in the selection of existing treatments. Rare leukemias pose additional challenges in this regard as samples may be hard to acquire and the underlying pathway found may not be attractive to drug development since so few individuals are affected. The aim of this thesis is to further characterize the JAK/STAT signaling pathway in LGL leukemia. By using a combination of genomic and molecular biology methods, we can better understand what role this dysregulated pathway plays in the pathogenesis of LGL leukemia. Whole genome sequencing was used on both a rat NK-LGL leukemia model (Chapter 2) and on T-LGL leukemia patient samples (Chapter 3). In both of these chapters, we discovered novel JAK1 and STAT3 mutations that were functionally characterized. First, a novel mutation in JAK1 was found in a spontaneously occurring LGL leukemia rat model cell line, RNK-16. This significant discovery revealed several things. This confirmed the significance of JAK/STAT pathway in a spontaneous LGL leukemia model and this activating mutation increased downstream STAT signaling. Interestingly, this mutation was the only oncogene mutation confirmed in ex vivo RNK-16 leukemia material, meaning this mutation was there from the beginning and may explain in part, why it is more aggressive than the other strains. Lastly, we tested the efficacy of a peptide that blocks IL-15 signaling pathway (Chapter 4). Our pre clinical data showed the induction of apoptosis in LGL leukemia cells and the reduction of downstream pathways relevant to the pathogenesis of LGL leukemia. This resulted in the start of a phase 1/2 clinical trial that enrolled 20 LGL leukemia patients spanning four medical centers across the US. This trial showed clinical efficacy in a few patients, indicating a need for further studies and to continue the fight for a cure for LGL leukemia.

PHD (Doctor of Philosophy)

LGL leukemia; Cancer ; JAK1; STAT3; BNZ-1; IL-15; Somatic mutation

English

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2020-04-30