Double jeopardy from a single translocation: deletions of the derivative chromosome 9 in chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is characterized by formation of a BCR-ABL fusion gene, usually as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. Recently the development of new fluorescence insitu hybridization (FISH) techniques has allowed identification of unexpected deletions of the reciprocal translocation product, the derivative chromosome 9, in 10% to 15% of patients with CML. These deletions are large, span the translocation breakpoint, and occur at the same time as the Ph translocation. Such deletions therefore give rise to previously unsuspected molecular heterogeneity from the very beginning of this disease, and there is mounting evidence for similar deletions associated with other translocations. Several studies have demonstrated that CML patients who carry derivative chromosome 9 deletions exhibit a more rapid progression to blast crisis and a shorter survival. Deletion status is independent of, and more powerful than, the Sokal and Hasford/European prognostic scoring systems. The poor prognosis associated with deletions is seen in patients treated with hydroxyurea or interferon, and preliminary evidence suggests that patients with deletions may also have a worse outcome than nondeleted patients following stem cell transplantation or treatment with imatinib. Poor outcome cannot be attributed to loss of the reciprocal ABL-BCR fusion gene expression alone, and is likely to reflect loss of one or more critical genes within the deleted region. The molecular heterogeneity associated with the Philadelphia translocation provides a new paradigm with potential relevance to all malignancies associated with reciprocal chromosomal translocations and/or fusion gene formation. IntroductionChronic myeloid leukemia (CML) is a clonal hematologic malignancy that arises in the stem cell compartment. [1][2][3] Its molecular hallmark is the BCR-ABL fusion gene, 4,5 which usually occurs as the result of the Philadelphia (Ph) translocation involving the long arms of chromosomes 9 and 22. 6 The chimeric BCR-ABL gene encodes a constitutively activated protein tyrosine kinase, which leads to the activation of multiple signaling pathways, with profound effects on cell cycle, adhesion, and apoptosis. 2,3 In murine transgenic and retroviral transduction models, expression of BCR-ABL has been shown to be both sufficient for initiation and necessary for maintenance of a leukemic phenotype. [7][8][9][10][11][12][13][14] The natural history of CML follows a biphasic pattern with an initial chronic phase, which is often asymptomatic. This is inevitably followed by progression of the disease through an ill-defined stage termed accelerated phase to the terminal blast crisis. During chronic phase, the myeloid compartment is expanded but the cells retain their capacity to differentiate and function normally, and drug treatment is usually effective. By contrast, blast crisis is characterized by loss of differentiation capacity together with refractoriness to therapy and is associated with the acquisit...

Derivative chromosome 9 deletions are a significant feature of childhood Philadelphia chromosome positive acute lymphoblastic leukaemia

“…6 This technique allows for the detection and (where metaphases are present) location of both the BCR/ABL and ABL/BCR fusion genes. 7 In cells with a deletion, one or both of the signals corresponding to ABL/BCR are absent from the der (9). These findings were correlated with molecular studies indicating loss of the ABL/BCR fusion transcript in a number of patients.…”

Imatinib improves but may not fully reverse the poor prognosis of patients with CML with derivative chromosome 9 deletions

“…These systems are equivalent, except in their ability to detect deletions of chromosome 22 sequences in addition to deletions of sequences from the derivative chromosome 9. 31 In this regard, deletions solely of chromosome 22 sequences may have been missed in the 53 patients analyzed with the ES probe system. The rates of CHR, MCR, and CCR achieved in patients according to deletion status and disease phase are shown when available.…”

“…The second possibility is that the size of the cohort of newly diagnosed patients is simply too small to show any differences. The presumed molecular mechanism underlying the deletions is loss of a tumor suppressor gene, 31 and, because of the heterogeneity of the size and type (chromosome 9 and/or 22 sequence loss) of deletions, it is likely that only a subgroup of patients with deletions actually carry this molecular lesion. However, the third explanation is that the molecular lesion associated with deletion of derivative chromosome 9 sequences may require time to irrevocably drive disease progression, irrespective of imatinib treatment, and however early it is started.…”

Downregulated expression of genes mapping on chromosome 9 in chronic myeloid leukemia cases bearing genomic deletions on der(9)

“…The most probable hypothesis is that microdeletions could be associated with the loss of tumor suppressor genes or genes implicated in cell-cycle regulation, resulting in a proliferative advantage of the leukemic clone. 4 This phenomenon may act by a gene dosage effect known as haploinsufficiency: mutation or loss of a single allele may be sufficient to elicit a cellular phenotype that leads to tumorigenesis without the inactivation of the second allele. The aim of our study was therefore to assess whether the sequences loss on der(9) in CML patients was associated with a gene product decrease.…”

“…To study these differences in the expression profiles of leukemic cells, we selected 26 genes (5 genes from Staal et al 3 and 21 top-ranked genes from Beesley et al 4 ) that showed differential expression in diagnosis and relapse, originating from the above-mentioned studies that compared gene expression levels between diagnosis and relapse in B-precursor ALL.…”