Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Westerman, David × Author: Kankanige, Yamuna ×

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    Single-cell sequencing demonstrates complex resistance landscape in CLL and MCL treated with BTK and BCL2 inhibitors
    Thompson, ER ; Nguyen, T ; Kankanige, Y ; Markham, JF ; Anderson, MA ; Handunnetti, SM ; Thijssen, R ; Yeh, PS-H ; Tam, CS ; Seymour, JF ; Roberts, AW ; Westerman, DA ; Blombery, P (ELSEVIER, 2022-01-25)
    The genomic landscape of resistance to targeted agents (TAs) used as monotherapy in chronic lymphocytic leukemia (CLL) is complex and often heterogeneous at the patient level. To gain insight into the clonal architecture of acquired genomic resistance to Bruton tyrosine kinase (BTK) inhibitors and B-cell lymphoma 2 (BCL2) inhibitors in CLL, particularly in patients carrying multiple resistance mutations, we performed targeted single-cell DNA sequencing of 8 patients who developed progressive disease (PD) on TAs (either class). In all cases, analysis of single-cell architecture revealed mutual exclusivity between multiple resistance mutations to the same TA class, variable clonal co-occurrence of multiple mutations affecting different TAs in patients exposed to both classes, and a phenomenon of multiple independent emergences of identical nucleotide changes leading to canonical resistance mutations. We also report the first observation of established BCL2 resistance mutations in a patient with mantle cell lymphoma (MCL) following PD on sequential monotherapy, implicating BCL2 as a venetoclax resistance mechanism in MCL. Taken together, these data reveal the significant clonal complexity of CLL and MCL progression on TAs at the nucleotide level and confirm the presence of multiple, clonally independent, mechanisms of TA resistance within each individual disease context.
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    Quantitation of CMV Specific T-Cell Expansion Using T Cell Receptor Beta Locus Deep Sequencing to Identify Patients at Risk of Viral Complications
    Kuzich, JA ; Kankanige, Y ; Guinto, J ; Ryland, G ; McBean, M ; Thompson, E ; Wong, E ; Koldej, R ; Collins, J ; Westerman, D ; Ritchie, DS ; Blombery, P (ELSEVIER SCIENCE INC, 2020-03)
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    Clonal independence of JAK2 and CALR or MPL mutations in comutated myeloproliferative neoplasms demonstrated by single cell DNA sequencing
    Thompson, ER ; Nguyen, T ; Kankanige, Y ; Yeh, P ; Ingbritsen, M ; McBean, M ; Semple, T ; Arnau, GM ; Burbury, K ; Lee, N ; Khot, A ; Westerman, D ; Blombery, P (FERRATA STORTI FOUNDATION, 2021-01)
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    Characterisation of immune checkpoints in Richter syndrome identifies LAG3 as a potential therapeutic target
    Gould, C ; Lickiss, J ; Kankanige, Y ; Yemeni, S ; Lade, S ; Gandhi, MK ; Chin, C ; Yannakou, CK ; Villa, D ; Slack, GW ; Markham, JF ; Tam, CS ; Nelson, N ; Seymour, JF ; Dickinson, M ; Neeson, PJ ; Westerman, D ; Blombery, P (WILEY, 2021-10)
    Richter syndrome (RS), an aggressive lymphoma occurring in the context of chronic lymphocytic leukaemia/small lymphocytic lymphoma, is associated with poor prognosis when treated with conventional immunochemotherapy, therefore, improved treatments are required. Immune checkpoint blockade has shown efficacy in some B-cell malignancies and modest responses in early clinical trials for RS. We investigated the immune checkpoint profile of RS as a basis to inform rational therapeutic investigations in RS. Formalin-fixed, paraffin-embedded biopsies of RS (n = 19), de novo diffuse large B-cell lymphoma (DLBCL; n = 58), transformed indolent lymphomas (follicular [tFL], n = 16; marginal zone [tMZL], n = 24) and non-transformed small lymphocytic lymphoma (SLL; n = 15) underwent gene expression profiling using the NanoString Human Immunology panel. Copy number assessment was performed using next-generation sequencing. Immunohistochemistry (IHC) for LAG3 and PD-1 was performed. LAG3 gene expression was higher in RS compared to DLBCL (P = 0·0002, log2FC 1·96), tFL (P < 0·0001, log2FC 2·61), tMZL (P = 0·0004, log2FC 1·79) and SLL (P = 0·0057, log2FC 1·45). LAG3 gene expression correlated with the gene expression of human leukocyte antigen Class I and II, and related immune genes and immune checkpoints. IHC revealed LAG3 protein expression on both malignant RS cells and tumour-infiltrating lymphocytes. Our findings support the investigation of LAG3 inhibition to enhance anti-tumour responses in RS.