Chromosomes and causation of human cancer and leukemia: XL. The Ph1 and other translocations in CML

Sandberg, Avery A.

doi:10.1002/1097-0142(19801115)46:10<2221::aid-cncr2820461019>3.0.co;2-8

Cited by 119 publications

(31 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Two previous studies also noted a shorter survival in variant Ph-positive CML (Potter et al, 1981;Bernstein et al, 1984). Other groups, however, failed to support these findings (Sandberg, 1980;De Braekeleer, 1987). It is reasonable to speculate that, in the latter studies, the cohorts of variant patients were too small to detect a statistically significant survival difference or contained an unusually low proportion of deleted patients.…”

Section: Discussionmentioning

confidence: 77%

“…Previous survival analyses of variant Ph-positive CML, however, have yielded contradictory results. Several reports have noted a significantly worse prognosis in variant Ph-positive patients than in those with classical t(9;22) (Potter et al, 1981;Bernstein et al, 1984), however, other studies have failed to support this theory (Sandberg, 1980;De Braekeleer, 1987).…”

mentioning

confidence: 96%

See 1 more Smart Citation

Survival implications of molecular heterogeneity in variant Philadelphia‐positive chronic myeloid leukaemia

Reid¹,

Huntly²,

Grace³

et al. 2003

Br J Haematol

View full text Add to dashboard Cite

Summary. The BCR-ABL fusion in chronic myeloid leukaemia (CML) is generated by the Philadelphia (Ph) translocation t(9;22) or, in 10% of patients, variants thereof (vPh). Deletion encompassing the reciprocal product (ABL-BCR) from the derivative chromosome 9 [der(9)] occurs in 15% of all patients, but with greater frequency in vPh patients. Reports of physical separation of ABL-BCR in nondeleted patients, as well as evolution from classical to variant Ph, introduce further heterogeneity to the vPh subgroup and raise the possibility that such translocations may herald disease progression. Survival analyses, however, have thus far yielded contradictory results. We assessed the frequency of der(9) deletions, ABL-BCR abrogation, cytogenetic evolution and cryptic rearrangement in a large cohort of 54 patients with vPh CML. Deletions encompassing ABL-BCR were detected in 37% of patients, consistent with a model in which a greater number of chromosome breaks increases the risk of genomic loss. The components of ABL-BCR were physically separated in a further 52% of patients while fused in the remaining 11%. Evolution from classical to vPh was demonstrated in three patients. The difference in survival, as indicated by Kaplan-Meier analysis, was marked between classical and vPh patients (105 vs 60 months respectively; P ¼ 0AE0002). Importantly, this difference disappeared when patients with deletions were removed from the analysis. Our study showed that, despite the existence of several levels of genomic heterogeneity in variant Ph-positive CML, der(9) deletion status is the key prognostic factor.

show abstract

Section: Discussionmentioning

confidence: 77%

mentioning

confidence: 96%

Survival implications of molecular heterogeneity in variant Philadelphia‐positive chronic myeloid leukaemia

Reid¹,

Huntly²,

Grace³

et al. 2003

Br J Haematol

View full text Add to dashboard Cite

show abstract

“…32,33,39,40 Patients with a variant Ph translocation have a more than 3-fold increase in the frequency of deletions, although patients with a deletion still represent a minority (39%) of patients with a variant Ph translocation. Differences in the proportion of patients carrying a deletion are therefore likely to account for previous controversy concerning the prognostic significance of variant compared to classical Ph translocations.…”

Section: Discussionmentioning

confidence: 99%

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

Huntly

Reid²,

Bench³

et al. 2001

Blood

220

196

View full text Add to dashboard Cite

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...

show abstract

“…While extensive study of chromosomal abnormalities in ATL patients and in HTLV-I infected/transformed cells has demonstrated a wide variety of clonal chromosomal abnormalities with complicated karyotypes in both numbers and structures, no specific karyotypic abnormalities have been associated with ATL cells (Sandberg, 1980;Kibler and Jeang, 2001). Although chromosomal abnormalities appear to be random in ATL cells, certain types of aberrations, including duplications, deletions, translocations, rearrangements and aneuploidy, are commonly observed in these cells and it remains possible that specific chromosomal alterations may be responsible for the development of ATL.…”

Section: Genome Instability and Htlv-i Infectionmentioning

confidence: 99%

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

2005

View full text Add to dashboard Cite

Chromosomes and causation of human cancer and leukemia: XL. The Ph1 and other translocations in CML

Cited by 119 publications

References 37 publications

Survival implications of molecular heterogeneity in variant Philadelphia‐positive chronic myeloid leukaemia

Survival implications of molecular heterogeneity in variant Philadelphia‐positive chronic myeloid leukaemia

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

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

Contact Info

Product

Resources

About