Sir Peter MacCallum Department of Oncology - Theses

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End date: 2016 × Start date: 2016 × Type: PhD thesis × Subject: Acute Lymphoblastic Leukemia ×

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    Investigating the role of CRLF2 & JAK2 in B-cell Acute Lymphoblastic Leukemia (B-ALL)
    Kim, Sang Kyu ( 2016)
    B-cell acute lymphoblastic leukemia (B-ALL) is a malignant neoplasm of B-lymphoid progenitor cells and accounts for approximately 70% of all childhood ALL (Loh and Mullighan, 2012). Overall clinical outcomes for ALL patients have seen remarkable improvements over the last 50 years predominantly through the optimization of conventional chemotherapeutic regimens (Pui et al., 2008). However, BCR-ABL1-like B-ALL nevertheless remains associated with dismal prognosis, highlighting an urgent clinical need for alternative treatment strategies for this genetic subset of B-ALL (Yeoh et al., 2002). Despite significant advances in the understanding of the genetic basis of BCR-ABL1-like B-ALL, the lack of animal models has significantly debilitated our ability to comprehensively investigate the biology of this devastating disease (Roberts et al., 2012). Accordingly, in this study we pursued the development of novel syngeneic mouse models of BCR-ABL1-like B-ALL to initially establish a clinically relevant setting to unravel and understand the therapeutic vulnerabilities of the disease. Multiple genetic alterations have been shown to frequently co-occur in this subset of B-ALL, including CRLF2 rearrangements, activating JAK2 mutations and/or IKZF1 alterations (Harvey et al., 2010). Using a mosaic approach, we successfully modelled the cooperation of (Eµ-Crlf2 mediated) surface CRLF2 receptor overexpression and B-ALL associated pathogenic JAK2 mutants (JAK2R683G and JAK2P933R mutants) during leukemogenesis. The resulting leukemias were serially transplantable and displayed many of the clinical and molecular attributes exhibited by human CRLF2-rearranged/mutant JAK2-driven B-ALLs. In particular, biochemical characterization of the resulting leukemias demonstrated exquisite similarities with those seen in the human disease, including JAK2-dependent constitutive activation of the STAT5 and PI3K signaling pathways (Tasian et al., 2012). Using an RNAi-mediated approach we subsequently unravelled an unexpected role for oncogenic JAK2 in regulating cell cycle progression independent of apoptosis in both murine and human models of CRLF2/mutant JAK2-driven leukemia. Consequent interrogation for mechanisms underlying JAK2-independent proliferation revealed a potential role of MYC and/or genome wide upregulation of its target genes in driving persistent proliferation upon shRNA-mediated depletion of JAK2 alone.