Research Program Overview:
Chronic myeloid leukaemia (CML) is fatal if untreated. Due to significant advances in drug therapy, patients now sustain long term survival. However, 20-30% of patients fail therapy. Newer, more potent drugs are continually being developed to treat or limit drug resistance. However, these drugs are associated with higher cardiovascular toxicity and have not shown a survival advantage. It is currently not possible to identify patients at the time of diagnosis who are destined to fail therapy. Therefore, it is not possible to determine which patients could benefit from more potent drugs despite the increased risk.
Our research is focussed on the development and clinical evaluation of novel molecular approaches to understand and predict drug resistance for patients with CML. The pace of discovery of resistance mechanisms is now substantially more rapid due to new technology. We can now simultaneously examine hundreds to thousands of genes to find the causes of drug resistance and to identify new drug targets. Working with pharmaceutical companies and monitoring patients enrolled in international clinical trials we aim to discover the molecular factors associated with treatment failure. Our objective is to translate our work into clinical practice to improve risk stratification and enhance therapy decisions for better outcomes for patients with CML.
Current Research Projects:
- Defining high risk mutations at diagnosis of CML and at treatment failure.
- Establish whether first-line treatment with potent tyrosine kinase inhibitors overcomes the risk conferred by additional genomic abnormalities at diagnosis.
- Develop enhanced bioinformatic tools and machine learning for improved risk stratification in CML.
- Examine the association between clonal haematopoiesis and late relapse for patients with treatment-free remission.
- Develop a clinical grade RNA-based method for comprehensive and sensitive characterisation of diverse mutation types
Select Recent Publications:
- Shanmuganathan N, Wadham C, Thomson D, Shahrin NH, Vignaud C, Obourn V, Chaturvedi S, Yang F, Feng J, Saunders V, Kok CH, Yeung D, King RM, Kenyon RR, Lin M, Wang P, Scott H, Hughes T, Schreiber AW, Branford S. RNA-Based targeted gene sequencing improves the diagnostic yield of mutant detection in chronic myeloid leukemia. The Journal of Molecular Diagnostics. 2022;24(7):803-822.
- Fernandes A, Shanmuganathan N, Branford S. Genomic mechanisms influencing outcome in chronic myeloid leukemia. Cancers. 2022;14(3):620.
- Shanmuganathan N, Pagani IS, Ross DM, Park S, Yong ASM, Braley JA, Altamura HK, Hiwase DK, Yeung DT, Kim D-W, Branford S*, Hughes TP*. Early BCR-ABL1 kinetics are predictive of subsequent achievement of treatment-free remission in chronic myeloid leukemia. Blood. 2021;137(9):1196-1207. * Equal senior author.
- Thomson DW, Shahrin NH, Wang PPS, Wadham C, Shanmuganathan N, Scott HS, Dinger ME, Hughes TP, Schreiber AW, Branford S. Aberrant RAG-mediated recombination contributes to multiple structural rearrangements in lymphoid blast crisis of chronic myeloid leukemia. Leukemia. 2020;34(8):2051-2063.
- Branford S, Kim DDH, Apperley JF, Eide CA, Mustjoki S, Ong ST, Nteliopoulos G, Ernst T, Chuah C, Gambacorti-Passerini C, Mauro MJ, Druker BJ, Kim D-W, Mahon F-X, Cortes J, Radich JP, Hochhaus A, Hughes TP. Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia. Leukemia. 2019;33(8):1835-1850.
- Shanmuganathan N, Braley JA, Yong ASM, Hiwase DK, Yeung DT, Ross DM, Hughes TP*, Branford S*. Modeling the safe minimum frequency of molecular monitoring for CML patients attempting treatment-free remission. Blood. 2019;134(1):85-89. * Equal senior author
- Branford S, Wang P, Yeung DT, Thomson D, Purins A, Wadham C, Shahrin NH, Marum JE, Nataren N, Parker WT, Geoghegan J, Feng J, Shanmuganathan N, Mueller MC, Dietz C, Stangl D, Donaldson Z, Altamura H, Georgievski J, Braley J, Brown A, Hahn C, Walker I, Kim SH, Choi SY, Park SH, Kim DW, White DL, Yong ASM, Ross DM, Scott HS, Schreiber AW, Hughes TP. Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease. Blood. 2018;132(9):948-961.
- Marum JE, Yeung DT, Purins L, Reynolds J, Parker WT, Stangl D, Wang PPS, Price DJ, Tuke J, Schreiber AW, Scott HS, Hughes TP, Branford S. ASXL1 and BIM germ line variants predict response and identify CML patients with the greatest risk of imatinib failure. Blood Advances. 2017;1(18):1369-1381.
- Wang PP, Parker WT, Branford S, Schreiber AW. BAM-matcher: a tool for rapid NGS sample matching. Bioinformatics. 2016;32(17):2699-2701.
- Parker WT, Yeung DTO, Yeoman AL, Altamura HK, Jamison BA, Field CR, Hodgson JG, Lustgarten S, Rivera VM, Hughes TP, Branford S. The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib. Blood. 2016;127(15):1870-1880.
- Deininger MW, Hodgson JG, Shah NP, Cortes JE, Kim D-W, Nicolini FE, Talpaz M, Baccarani M, Müller MC, Li J, Parker WT, Lustgarten S, Clackson T, Haluska FG, Guilhot F, Kantarjian HM, Soverini S, Hochhaus A, Hughes TP, Rivera VM, Branford S. Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients. Blood. 2016;127(6):703-712.
- Cross NC, White HE, Ernst T, …….. Hochhaus A, Branford S. Development and evaluation of a secondary reference panel for BCR-ABL1 quantification on the International Scale. Leukemia. 2016;30(9):1844–1852.
- Branford S. Molecular monitoring in chronic myeloid leukemia—how low can you go? ASH Education Program Book. 2016;2016(1):156-163.
- Branford S, Yeung DT, Parker WT, Roberts ND, Purins L, Braley JA, Altamura HK, Yeoman AL, Georgievski J, Jamison BA, Phillis S, Donaldson Z, Leong M, Fletcher L, Seymour JF, Grigg AP, Ross DM, Hughes TP. Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood. 2014;124(4):511-518.
- Parker WT, Phillis SR, Yeung DT, Hughes TP, Scott HS, Branford S. PCR-mediated recombination can lead to artificial chimera formation, which may pose as BCR-ABL1 compound mutations. Blood. 2013;122(21):4014.
- Branford S, Yeung DT, Ross DM, Prime JA, Field CR, Altamura HK, Yeoman AL, Georgievski J, Jamison BA, Phillis S, Sullivan B, Briggs NE, Hertzberg M, Seymour JF, Reynolds J, Hughes TP. Early molecular response and female sex strongly predict stable undetectable BCR-ABL1, the criteria for imatinib discontinuation in patients with CML. Blood. 2013;121(19):3818-3824.
- Parker WT, Yeoman AL, Jamison BA, Yeung DT, Scott HS, Hughes TP, Branford S. BCR-ABL1 kinase domain mutations may persist at very low levels for many years and lead to subsequent TKI resistance. Br J Cancer. 2013;109(6):1593-1598.
- Branford S. Monitoring after successful therapy for chronic myeloid leukemia. ASH Education Program Book. 2012;2012(1):105-110.
- Parker WT, Ho M, Scott HS, Hughes TP, Branford S. Poor response to second-line kinase inhibitors in chronic myeloid leukemia patients with multiple low-level mutations, irrespective of their resistance profile. Blood. 2012;119(10):2234-2238.
- Branford S, Yeung DT, Prime JA, Choi S-Y, Bang J-h, Park JE, Kim D-W, Ross DM, Hughes TP. BCR-ABL1 doubling times more reliably assess the dynamics of CML relapse compared with the BCR-ABL1 fold rise: implications for monitoring and management. Blood. 2012;119(18):4264-4271.
- Branford S, Kim D-W, Soverini S, Haque A, Shou Y, Woodman RC, Kantarjian HM, Martinelli G, Radich JP, Saglio G, Hochhaus A, Hughes TP, Müller MC. Initial molecular response at 3 months may predict both response and event-free survival at 24 months in imatinib-resistant or -intolerant patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase treated with nilotinib. J Clin Oncol. 2012;30(35):4323-4329.
- Parker WT, Lawrence RM, Ho M, Irwin DL, Scott HS, Hughes TP, Branford S. Sensitive detection of BCR-ABL1 mutations in patients with chronic myeloid leukemia after imatinib resistance is predictive of outcome during subsequent therapy. J Clin Oncol. 2011;29(32):4250-4259.