Large deletions at the t(9;22) breakpoint are common and may identify a poor-prognosis subgroup of patients with chronic myeloid leukemia

Abstract

The hallmark of chronic myeloid leukemia (CML) is theBCR-ABL fusion gene, which is usually formed as a result of the t(9;22) translocation. Patients with CML show considerable heterogeneity both in their presenting clinical features and in the time taken for evolution to blast crisis. In this study, metaphase fluorescence in situ hybridization showed that a substantial minority of patients with CML had large deletions adjacent to the translocation breakpoint on the derivative 9 chromosome, on the additional partner chromosome in variant translocations, or on both. The deletions spanned up to several megabases, had variable breakpoints, and could be detected by microsatellite polymerase chain reaction in unfractionated bone marrow and purified peripheral blood granulocytes. The deletions were likely to occur early and possibly at the time of the Philadelphia (Ph) chromosome translocation: deletions were detected at diagnosis in 11 patients, were found in all Ph-positive metaphases, and were more prevalent in patients with variant Ph chromosomes. Kaplan-Meier analysis showed a median survival time of 36 months in patients with a deletion; patients without a detectable deletion survived > 90 months. The survival-time difference was significant on log-rank analysis (P = .006). Multivariate analysis demonstrated that the prognostic importance of deletion status was independent of age, sex, percentage of peripheral blood blasts, and platelet count. Our data therefore suggest that an apparently simple, balanced translocation may result not only in the generation of a dominantly acting fusion oncogene but also in the loss of one or more genes that influence disease progression.

Deletion of sequences flanking the t(9;22) breakpoint: a secondary genetic event associated with loss of cytogenetic response to interferon in a Philadelphia‐positive chronic myeloid leukaemia patient

“…In June 2001, FISH analysis was done using the D-FISH BCR-ABL detection system (Appligene Oncor, UK) to assess whether chromosome 22 sequences had also been lost. Deletion involving both chromosomes 9 and 22 sequences was observed in 45% of cells, supporting the data of Sinclair et al (2000), who detected deletions involving chromosome 22 sequences in 14 out of 16 patients in whom deletion of chromosome 9 was observed. The genetic results obtained at diagnosis and during follow-up of the patient are summarized in Table I.…”

“…As previously described, these deletions may occur as an early event, at the time of the Ph translocation formation, as Loss of both chromosome 9 and chromosome 22 sequences was detected on derivate 9 chromosome. they have mostly been detected at diagnosis and identified in all Ph metaphases (Dewald et al, 1999;Herens et al, 2000;Sinclair et al, 2000;Cohen et al, 2001). Our unpublished results also support this concept, as we have identified these deletions in all Ph-positive metaphases from diagnostic samples in seven CML patients.…”

“…Although deletions flanking the t(9;22) translocation have been identified before (Dewald et al, 1999;Herens et al, 2000;Sinclair et al, 2000), little is known about their timing and the mechanisms involved in their origin.…”

“…The genetic mechanisms involved in the clinical heterogeneity of the disease and in its progression from a chronic phase to an accelerated phase and blast crisis are poorly understood (Sokal et al, 1984). Sinclair et al (2000) and Herens et al (2000) reported a previously unrecognized form of genetic heterogeneity among patients with CML. They found that deletions resulting in loss of chromosome 9 and 22 sequences flanking the translocation breakpoint on the derivate 9 chromosome were associated with a poor prognosis.…”

Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study

“…Fusion-signal FISH was highly effective for the detection of BCR/ABL rearrangements. Although it is now accepted that the DF probe is a more accurate and sensitive method for the detection of the BCR/ABL rearrangements, as well as revealing the presence of deletions involving ABL/BCR on the der(9)t(9;22) (Sinclair et al, 2000;Primo et al, 2003;Robinson et al, 2005), the SF probe provides reliable detection of the fusion. If, in the future, deletions involving ABL/BCR are shown to be significant in terms of prognosis in ALL, as suggested by others (Kolomietz et al, 2001;Reid et al, 2002;Specchia et al, 2003), it will be important to investigate all positive cases with the DF probe.…”