Deletions of the derivative chromosome 9 occur at the time of the Philadelphia translocation and provide a powerful and independent prognostic indicator in chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is characterized by formation of the BCR-ABL fusion gene, usually as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. Large deletions on the derivative chromosome 9 have recently been reported, but it was unclear whether deletions arose during disease progression or at the time of the Ph translocation. Fluorescence in situ hybridization (FISH) analysis was used to assess the deletion status of 253 patients with CML. The strength of deletion status as a prognostic indicator was then compared to the Sokal and Hasford scoring systems. The frequency of deletions was similar at diagnosis and after disease progression but was significantly increased in patients with variant Ph translocations. In patients with a deletion, all Ph ؉ metaphases carried the deletion. The median survival of patients with and without deletions was 38 months and 88 months, respectively (P ‫؍‬ .0001). By contrast the survival difference between Sokal or Hasford high-risk and non-high-risk patients was of only borderline significance (P ‫؍‬ .057 and P ‫؍‬ .034). The results indicate that deletions occur at the time of the Ph translocation. An apparently simple reciprocal translocation may therefore result in considerable genetic heterogeneity ab initio, a concept that is likely to apply to other malignancies associated with translocations. Deletion status is also a powerful and independent prognostic factor for patients with CML. IntroductionChronic myeloid leukemia (CML) is a clonal hematologic malignancy that results from transformation of a multipotent hemopoietic stem cell. [1][2][3] The molecular hallmark of CML is the formation of a BCR-ABL fusion gene, usually formed as a consequence of the Philadelphia (Ph) translocation involving chromosomes 9 and 22. 4-6 BCR-ABL plays a pivotal role in the pathogenesis of CML and its formation is likely to represent the initiating event. In support of this concept transgenic and retroviral transduction studies have demonstrated that expression of BCR-ABL in murine bone marrow cells resulted in leukemia, with some cases closely resembling CML. [7][8][9][10][11][12][13] In one recent transgenic model the leukemia could be reversed by down-regulating BCR-ABL. 14 Chronic myeloid leukemia is a biphasic disease with an initial chronic phase that is readily controlled. However, this is followed by an ill-defined accelerated phase, and then a terminal blastic phase that resembles an acute leukemia, which is usually refractory to therapy. Transformation to blast crisis is accompanied by secondary cytogenetic changes in about 85% of cases, 15 but the molecular basis for this transformation is poorly understood. A number of molecular changes have been identified in a minority of cases of blast crisis, including mutations or deletions of p53, p16 INKA , and the retinoblastoma protein, and mutation or overexpression of Ras and EVI-1. 1,2 However, none provide a method for prospectively distinguishing those patients who will progress rapidly to blast...

Genomic segmental duplications on the basis of the t(9;22) rearrangement in chronic myeloid leukemia

“…In this paper, the involvement of SDs was proposed to explain the recurrent t(9;22) translocation in CML and the genomic deletions that could accompany the rearrangement. In fact, several groups have previously identified der(9) deletions next to translocation breakpoints as a frequent feature of patients with CML (Sinclair et al, 2000;Huntly et al, 2001;Kolomietz et al, 2001;Storlazzi et al, 2002;Specchia et al, 2004;Albano et al, 2007). To date, the characterization of deletions breakpoints has shown that breaks are scattered throughout large genomic regions, Figure 1 Bioinformatic studies performed on the chromosomes 9 and 22 analyzed regions.…”

“…However, the exact role of this duplicon in mediating the t(9;22) rearrangement remained mostly speculative. Moreover, it is well known that in 10-18% of patients with CML the t(9;22) is an unbalanced rearrangement, because genomic sequences of chromosomes 9 and 22 are lost during the translocation (Sinclair et al, 2000;Huntly et al, 2001;Kolomietz et al, 2001;Storlazzi et al, 2002). The mechanism on the basis of these genomic microdeletions still remains unclear.…”

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

“…21 None of the standard medical treatments appear to improve the outcome of patients with deletions of the derivative chromosome 9. 14,15 Moreover, in one study there was also an increased rate of relapse in patients with deletions following allografting. 14 Although the numbers of patients in this study were small (12 patients with deletions and 58 patients who lacked deletions), this finding suggests that allografting may be less effective in achieving disease eradication in patients with deletions of the derivative chromosome 9.…”

“…10,13,15 They are associated with an extremely poor prognosis, with those patients who carry them having shorter length of chronic phase, earlier disease transformation, and shorter survival. 14,15 Also, in a direct comparison, deletion status was a far more powerful prognostic indicator than either the commonly used Sokal or Hasford scores. 16,17 Conventional drug treatment for chronic-phase CML includes hydroxyurea and interferon-␣ with or without cytosine arabinoside.…”

“…[10][11][12][13][14][15] These deletions span the translocation breakpoint, often involve both chromosome 9 and 22 sequences, are large, sometimes measuring many megabases, and occur at the same time as the formation of the Philadelphia translocation. 10,13,15 They are associated with an extremely poor prognosis, with those patients who carry them having shorter length of chronic phase, earlier disease transformation, and shorter survival. 14,15 Also, in a direct comparison, deletion status was a far more powerful prognostic indicator than either the commonly used Sokal or Hasford scores.…”