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Leukaemia Unit, Genetic and Molecular Pathology

Leukaemia Unit, Genetic and Molecular Pathology

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.

Recent publications

  1. Branford S and Shanmuganathan N. NGS in CML - New standard diagnostic procedure? Hemasphere. 2019.

  2. Branford S, Kim D, Apperley J, Eide CA, Mustjoki S, Ong ST, Nteliopoulos G, Ernst T, Chuah C, Gambacorti-Passerini C, Mauro M, Druker B, Kim D, Mahon F, Cortes J, Radich J, Hochhaus A, Hughes T. Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia. Leukemia. 2019.

  3. Shanmuganathan N, Braley JA, Yong AS, Hiwase DK, Yeung DT, Ross DM, Hughes TP, Branford S. Modelling the safe minimum frequency of molecular monitoring for CML patients attempting treatment-free remission. Blood. 2019. [Epub ahead of print]

  4. Singhal D, Wee LY, Kutyna M, Chhetri R, Geoghegan J, Schreiber A, Feng J, Wang P, Babic M, Parker W, Hiwase S, Edwards S, Moore S, Branford S, Kuzmanovic T, Singhal N, Gowda R, Brown A, Arts P, To LB, Bardy P, Lewis I, D'Andrea R, Maciejewski J, Scott HS, Hahn C, D H. The mutational burden of therapy-related myeloid neoplasms is similar to primary myelodysplastic syndrome but has a distinctive distribution. Leukemia. 2019. Accepted.

  5. Magistroni V, Mauri M, D'Aliberti D, Mezzatesta C, Crespiatico I, Nava M, Fontana D, Sharma N, Parker W, Schreiber A, Yeung DT, Pirola A, Redaelli S, Massimino L, Wang P, Khandelwal P, Citterio S, Viltadi M, Bombelli S, Rigolio R, Perego R, Boultwood J, Morotti A, Saglio G, Kim D-W, Branford S, Gambacorti-Passerini C, Piazza R. De novo UBE2A mutations are recurrently acquired during chronic myeloid leukemia progression and interfere with myeloid differentiation pathways. Haematologica. 2019. [Epub ahead of print]

  6. Ross DM, Pagani I, Irani Y, Clarson J, Leclercq T, Dang P, McLean J, Saunders V, Carne L, Reynolds J, Ritchie D, White D, Branford S, Hughes TP, Yong A. Lenalidomide maintenance treatment after imatinib discontinuation: results of a phase 1 clinical trial in chronic myeloid leukaemia. British Journal of Haematology 2019. [Epub ahead of print]

  7. Lasica M, Willcox A, Kate K, Ross DM, Branford S, Butler J, Filshie R, Januszewicz H, Joske D, Mills A, Simpson D, Tam C, Taylor K, Watson AM, Wolf M, Grigg A. The effect of tyrosine kinase inhibitor interruption and interferon use on pregnancy outcomes and long term disease control in chronic myeloid leukaemia. Leukaemia and Lymphoma. 2019. [Epub ahead of print]

  8. Shanmuganathan N, Branford S, Hughes TP, Hiwase D. Bone marrow fibrosis associated with long-term imatinib therapy: resolution after switching to a second-generation TKI.Blood Advances. 2019;3(3):370-374.

  9. Ross DM, Pagani I, Shanmuganathan N, Kok CH, Seymour J, Mills A, Filshie R, Arthur C, Dang P, Saunders V, Braley J, Yong A, Yeung D, White D, Grigg A, Schwarer A, Branford S,Hughes T. Long-term treatment-free remission of chronic myeloid leukemia with falling levels of residual leukemic cells. Leukemia. 2018; 32(12):2572-2579.

  10. Pagani IS, Dang P, Kommers IO, Goyne JM, Nicola M, Saunders VA, Braley J, White DL, Yeung DT, Branford S, Hughes TP, Ross DM. BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia.Haematologica. 2018;103(12):2026-2032.

  11. Branford S, Wang P, Yeung D, Thomson D, Purins A, Wadham C, Shahrin NH, Marum J, Nataren N, Parker W, Geoghegan J, Feng J, Shanmuganathan N, Mueller M, Deitz C, Stangl D, Donaldson,1 Altamura H, Georgievski J, Braley J, Brown A, Hahn C, Walker I, Kim SH, Choi SY, Park SH, Kim DW, White D, Yong A, Ross D, Scott H, Schreiber A, Hughes T. Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high risk disease. Blood. 2018;132:948-961.

  12. Eadie LN, Saunders VA, Branford S, White DL, Hughes TP. The new allosteric inhibitor asciminib is susceptible to resistance mediated by ABCB1 and ABCG2 overexpression in vitro. Oncotarget. 2018;9(17):13423-13437.

  13. Hiwase D, Tan P, D'Rozario J, Taper J, Powell A, Irving I, Wright M, Branford S, Yeung DT, Anderson L, Gervasio O, Levetan C, Roberts W, Solterbeck A, Traficante R, Hughes T. Efficacy and safety of nilotinib 300 mg twice daily in patients with chronic myeloid leukemia in chronic phase who are intolerant to prior tyrosine kinase inhibitors: Results from the Phase IIIb ENESTswift study. Leuk Res. 2018;67:109-115.

  14. Hughes TP, Leber B, Cervantes F, Spector N, Pasquini R, Clementino NCD, Schwarer AP, Dorlhiac-Llacer PE, Mahon FX, Rea D, Guerci-Bresler A, Kamel-Reid S, Bendit I, Acharya S, Glynos T, Dalal D, Branford S, Lipton JH. Sustained deep molecular responses in patients switched to nilotinib due to persistent BCR-ABL1 on imatinib: final ENESTcmr randomized trial results. Leukemia. 2017;31:2529-2531.

  15. Ma L, Boucher JI, Paulsen J, Matuszewski S, Eide CA, Ou J, Eickelberg G, Press RD, Zhu LJ, Druker BJ, Branford S, Wolfe SA, Jensen JD, Schiffer CA, Green MR, Bolon DN. CRISPR-Cas9–mediated saturated mutagenesis screen predicts clinical drug resistance with improved accuracy. PNAS. 2017;114:11751-11756.

  16. Marum JE, Yeung DT, Purins L, Reynolds J, Parker WT, Stangl D, Wang PS, Price DJ, Tuke SJ, Schreiber A, Scott HS, Hughes TP, Branford S. ASXL1 and BIM germline variants predict response and identify CML patients with the greatest risk of imatinib failure.Blood Advances. 2017;1:1369-1381.

  17. Wylie A, Schoepfer J, Jahnke W, Cowan-Jacob S, Loo A, Furet P, Marzinzik A, Pelle X, Donovan J, Zhu W, Buonamici S, Hassan Q, Lombardo F, Iyer D, Palmer M, Berellini G, Dodd S, Thohan S, Bitter H, Branford S, Ross D, Hughes T, Petruzzelli L, K. Vanasse G, Warmuth M, Hofmann F, Keen N, Sellers W. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature. 2017;543(7647):733-737.

  18. Hochhaus A, Larson, R, Guilhot F, Radich F, Branford S, Hughes T, Baccarani M, Deininger, M, Cervantes F, Fujihara S, Ortmann C, Menssen H, Kantarjian H, O'Brien S, Druker B. IRIS Final Analysis: Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med. 2017 376(10):917-927.

  19. Casolari D, Nguyen T, Butcher C, Iarossi D, Hahn C, Bray S, Neufing P, Parker W, Feng J, Maung K, Wee A, Vidovic L, Kok C, Bardy P, Branford S, Lewis I, Lane S, Scott H, Ross D, D'Andrea R. A novel, somatic, transforming mutation in the extracellular domain of Epidermal Growth Factor Receptor identified in myeloproliferative neoplasm. Scientific Reports. 2017;7:2467.

  20. 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;127:1870-1880.