The long-term goal of our research is to understand the molecular pathways that control the  clonal evolution of leukaemic stem cells  in human haematological malignancies, with a specific focus on aberrant JAK/STAT signalling. For these studies, we predominantly focus on a family of human cancers called the chronic myeloproliferative neoplasms (MPN), which harbour mutations that activate JAK/STAT pathways and provide a window into early stages of tumorigenesis that are often inaccessible in other cancers. To date, our work has illuminated mechanisms whereby aberrant JAK/STAT pathways influence diverse aspects of cell function, including DNA replication and repair, lineage fate choice and immune activity. We hope to apply these insights to the development of novel and non-toxic therapies that may prevent clonal evolution and disease progression.

Genomic instability in myeloid malignancies

Erosion of DNA repair competency accelerates clonal evolution, promotes chemotherapy resistance and correlates with poorer prognosis. However, how and why genome instability arises in some tumours remains unclear. This question of how genome instability arises during malignant transformation is often difficult to parse because genome integrity pathways are frequently already heavily compromised (eg. p53 loss) by the time a cancer diagnosis is made. In contrast, MPN can provide us a glimpse into how genome stability is regulated in a nascent neoplasm. Our previous work has shown that oncogenic non-receptor tyrosine kinases such as the JAK2V617F mutation commonly found in patients with myeloproliferative disorders causes stalling of replication forks during S-phase to engender a cellular state known as replication stress. Stalled replication forks are potentially mutagenic and can form DNA double-strand breaks and chromosomal rearrangements if improperly resolved. We have recently shown that RECQ helicases play a crucial role in maintaining genome integrity associated with oncogene-induced replication stress in chronic-phase disease. We have also identified subsets of patients whom are incapable of responding effectively to replication stress manifested by insufficient Chk1 activity, thereby promoting disease progression. By analysing the transcriptional and mutational profiles of these patients, we have begun to dissect the pathways crucial for DNA repair that are subverted during leukaemic progression.

 

Calreticulin mutations in MPN
In 2013, somatic mutations in the gene CALR was identified in ~30% of patients with the MPN subtypes essential thrombocythaemia (ET) and primary myelofibrosis (MF). CALR encodes a calcium-dependent ER-resident chaperone called calreticulin, and represents the first time that this class of proteins has been implicated in cancer. CALR mutations are mutually exclusive with other MPN lesions that activate JAK/STAT pathways (including JAK2V617F and MPLW515L), and gives rise to an alternative reading frame that encodes a mutation-specific novel C-terminal tail of calreticulin. However, the mechanism by which these mutations can promote MPN development remains unknown. In collaboration with the Astbury Biostructure Laboratories, we are undertaking a wide array of structural biology techniques to interrogate the impact of these mutations on the structure and function of the calreticulin protein. In particular, we are interested in the impact of CALR mutations on JAK/STAT activation and megakaryopoiesis. These insights may enable us to gain a deeper understanding into the biology behind these mutations and their role in MPN pathogenesis

 

Cancer: The Emperor of All Maladies

Ken Burns and Siddhartha Mukherjee talk about cancer

Introduction to MPN

Lecture by Professor Tony Green, University of Cambridge

© 2019 Edwin Chen