MG-144 When rare happens: Characterising atypical breakpoints in CML
| Autor: | Aly Karsan, Darko Curman, Mohamed Elemary, Elaine Law, Sean D. Young, Haji Chalchal, Mirjana Zarkovic |
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| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | Journal of Medical Genetics. 52:A13.1-A13 |
| ISSN: | 1468-6244 0022-2593 |
| DOI: | 10.1136/jmedgenet-2015-103577.33 |
| Popis: | Chronic Myeloid Leukaemia (CML) is a hematopoietic disorder characterised by an increased proliferation of predominantly the myeloid lineage in the bone marrow and consequently the accumulation of these cells in the blood. It is caused by a translocation between the q arms of chromosome 9 and 22 resulting in the fusion of the proximal portion of BCR (on chromosome 22) to the distal portion of ABL1 gene (chromosome 9). In most cases of CML, the translocation breakpoint occurs either downstream of BCR exon 13 or 14 and upstream of ABL1 exon 2 (major breakpoint). In a small proportion of CML patients, the breakpoint occurs downstream of BCR exon 1 (minor breakpoint). Patients with either the major or minor breakpoint are monitored in our laboratory using quantitative RT-PCR (Q-RTPCR) from peripheral blood derived RNA in order to assess response to tyrosine kinase inhibitor (TKI) therapy. Here we describe two cases of CML from Saskatchewan with rare, atypical breakpoints. In each case, peripheral blood derived RNA obtained at diagnosis was subjected to Q-RTPCR. Results revealed an estimated molecular burden far inferior to what would be expected of such a specimen. This discordance was investigated using conventional RTPCR using exon specific forward primers targeting BCR exons 1 through 12. For patient #1, the results revealed that the fusion point on BCR occurred downstream of BCR exon 8 and upstream of BCR exon 9 (i.e. in intron 8). Investigational sequencing studies on the PCR products seen in the RTPCR reaction revealed the presence of an atypical breakpoint involving BCR exon 8, SNRPD3 exon 3, and ABL1 exon 3 (b8s3a2 fusion variant). The second case was also subjected to exon-specific forward PCR which revealed the fusion point on BCR occurred downstream of BCR exon 6 and upstream of BCR exon 7. Sequencing analysis revealed that the patient had an in-frame b6a2 fusion variant. In addition, we describe a third Saskatchewan case in which the patient had developed resistance to treatment with imatinib. Sequential kinase domain sequencing studies revealed, in turn, that the patient evolved an imatinib resistant clone harbouring ABL1:p. Met244Val, followed by a clone in which ABL1 exon 04 encompassing codon 244 was deleted, followed by loss of the latter clone and re-emergence of ABL1:p. Met244Val. |
| Databáze: | OpenAIRE |
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