The fate of patients diagnosed with chronic myeloid leukaemia (CML) has changed dramatically over the last decade. The disease was invariably fatal, but the introduction of drug therapy that targets the genetic abnormality specific to the disease means that many patients can now have a normal life expectancy.
We are investigating the response to therapy by examining the genetic abnormality that causes the disease: the BCR-ABL1 gene. Specific therapy targets and kills the leukaemic cells containing BCR-ABL1. We monitor the kinetics of drug response by using molecular techniques to measure the levels of BCR-ABL1 mRNA. A rapid reduction of BCR-ABL1 is associated with the best long-term outcome, although this occurs in a minority of patients. We are investigating whether the heterogeneity of drug response is associated with variation in genes that initiate leukaemic cell death.
A major interest of ours is the sensitive detection of mutations within the BCR-ABL1 gene and genome-wide deep sequencing for the detection of mutated genes that lead to disease progression. We are currently developing techniques for the detection of an ultra-rare leukaemic signature using deep sequencing with single molecule barcodes. The aim is to determine if there is a level of leukaemia below which patients can safely cease drug therapy without rapid relapse.
Current research projects
- Characterising the rate of leukaemic cell death and the heterogeneity of response to tyrosine kinase inhibitor therapy: We are assessing the capacity of kinase inhibitors to initiate apoptosis with the aim of identifying patients at the time of diagnosis with an impaired apoptotic response. This may guide therapeutic decisions designed to avoid early disease progression.
- Defining the role of additional genomic mutations discovered in BCR-ABL1expressing cells. We are using powerful new genomic technologies, including next-generation sequencing and bioinformatic tools, to identify mutations at the time of diagnosis and/or at disease progression. We aim to define the role of these mutations in the disease process.
Branford S, DW Kim, S Soverini, A Haque, Y Shou, R Woodman, H. Kantarjian, G Martinelli, J Radich, G Saglio, A Hochhaus, T Hughes, M. Müller. "Initial molecular response at 3 months may predict both responses and event-free survival at 24 months in imatinib-resistant or –intolerant patients with philadelphia chromosome–positive chronic myeloid leukemia in chronic phase (CML-CP) treated with nilotinib." J Clin Oncology 30:4323-4329. (2012)
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 In Press (2014)
Branford S, Yeung DT, Parker WT, Roberts N, Purins L, Braley J, Altamura H, Yeoman A, Georgievski J, Jamison B, Phillis S, Donaldson Z, Leong M, Fletcher L, Seymour JF, Grigg A, 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 In Press (2014)
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 109:1593-1598. (2013)
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 121:3818-3824. (2013)
Parker, W. T., M. Ho, H. S. Scott, T. P. Hughes and S. Branford. "Poor response to second-line kinase inhibitors in chronic myeloid leukemia patients with multiple low-level mutations, irrespective of their resistance profile." Blood 119: 2234-2238. (2012)
Branford, S., D. T. Yeung, J. A. Prime, S. Y. Choi, J. H. Bang, J. E. Park, D. W. Kim, D. M. Ross and T. P. Hughes. "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 119: 4264-4271. (2012)