Mutation Assay : ABL Kinase Domain

CML is a haematopoietic stem cell disease characterised by the 9:22 translocation, which fuses BCR gene with the ABL gene. Imatinib is a 2-phenylamino pyrimidine that targets the ATP binding site of the ABL kinase domain and is a very effective drug for the majority of CML patients. However, proportions of patients respond partially or acquire clinical resistance after achieving a response. One of the mechanisms for resistance is the presence/acquisition of one or more point mutations’ in the ABL kinase domain region, the section that interacts and binds the Imatinib molecule. Mutations have been demonstrated in the catalytic and activation domains but the mutations tend to cluster in the highly conserved P loop region. A particular mutation, the T315I, produces complete resistance to Imatinib while some of the other mutations confer partial resistance and can be negated by an escalating dose regime. Patients with P-loop mutations tend to have a poor overall survival. Therefore it is necessary to examine the presence and type of mutations in patients who lack or show low level of response.
Sample type and Volume required: 
1-5 ml Bone marrow and/or 20ml peripheral blood in EDTA (purple top) tube. Presence of heparin anticoagulant will inhibit PCR applications. Clotted samples are unsuitable for RNA analysis. Samples must be clearly labelled with the patient's first name, surname, D.O.B, hospital number and the date the sample was taken.
Turnaround time: 
3 - 5 working days
Storage and transport: 
To be sent within 2 days and stored at room temperature. First class postage is adequate but samples must be shipped with packaging appropriate for UN 3373 samples following packing instruction 650. See link below for further details. Samples should be addressed to: Central Specimen Reception, Ground Floor, Bessemer Wing, King's College Hospital, Denmark Hill, London SE5 9RS, United Kingdom
Please contact Business Development for pricing enquiries
Time limit for extra tests: 
Test specific - please enquire.
HMDC Laboratory for Molecular Haemato-Oncology at King's College Hospital
020 7848 5809
King's College Hospital
Denmark Hill
London SE5 9RS
HMDC Department at King's College Hospital
020 3299 9000 ext 32414
c/o Central Specimen Reception
Blood Sciences Laboratory
Ground Floor Bessemer Wing
King’s College Hospital
Denmark Hill
London SE5 9RS
Mon-Fri, 9.00am-5.30pm
For clinical advice or interpretation of results, please contact the laboratory in the first instance.

Radich 2009 Blood 114: 3376-3381 Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN and Sawyers CL 2001 Clinical resis5tance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification Science 3 August Vol 293 P 876-880 Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J and Sawyers CL 2002 Mutiple BCR ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukaemia Cancer Cell vol 2 August 2002 p117-125 Corbin AS, La Rosee P, Stoffregen EP, Druker BJ and Deininger MW 2003 Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib, Blood, 1 June, Vol 101, number 11, p4611-4614 Branford S, Rudzki Z, Walsh S, Grigg A, Arthur C, Taylor K, Herrmann R, Lynch K and Hughes T, 2002 High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukaemia or Ph-positive acute lymphoblastic leukaemia who develop imatinib (STI571) resistance Blood, 1 May, Vol 99, number 9, p3472-3475 Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J, Taylor K, Herrmann R, Seymour JF, Arthur C, Joske D, Lynch K and Hughes T 2003 Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with poor prognosis, Blood, 1 July, vol 102 number 1 p276-283 Deininger MW, McGreevey L, Willis S, Bainbridge TM Druker BJ and Heinrich MC 2004 Detection of ABL kinase domain mutations with denaturing high-performance liquid chromatography Leukemia, 18 p864-871

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Last updated: 07/08/2015