The incidence, type, and subsequent evolution of 14 variant Ph1 translocations in 180 South African patients with Ph1-positive chronic myeloid leukemia

Bernstein, R; Pinto, M. R.; Wallace, C; Penfold, G.; Mendelow, B.

doi:10.1016/0165-4608(84)90034-7

Cited by 40 publications

(22 citation statements)

References 27 publications

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“…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).…”

Section: Discussionmentioning

confidence: 90%

“…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: 97%

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

Reid¹,

Huntly²,

Grace³

et al. 2003

Br J Haematol

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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.

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Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 97%

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

Reid¹,

Huntly²,

Grace³

et al. 2003

Br J Haematol

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“…by guest www.bloodjournal.org From no impact on the prognosis of CML. 29 Further, some studies have suggested that patients with variant translocations do have adverse outcomes, 4,[30][31][32][33] whereas others have reported that such translocations have no influence on response or survival. 6,8,[34][35][36][37] A previous analysis reported 44 cases with variant translocations in a series of 721 patients (4%) who had failed prior interferon therapy and were either in CP or the accelerated phase.…”

Section: Discussionmentioning

confidence: 99%

Variant Philadelphia translocations: molecular-cytogenetic characterization and prognostic influence on frontline imatinib therapy, a GIMEMA Working Party on CML analysis

Marzocchi

Castagnetti

Luatti

et al. 2011

Blood

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“…Instead, either simple aberrations involving chromosome band 22q11 or complex changes affecting 9q34 and 22q11, and a third, or even a fourth and a fifth, chromosome were found [40, 41, 42, 43, 44, 45, 46, 47]. It was initially debated whether these variant rearrangements, found in 2–10% of larger series of Ph-positive CML [5, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61], had any specific phenotypic impact. Potter et al [55]reported that the CP duration was significantly shorter for patients with CML with nonstandard Ph chromosomes than for those with t(9;22), whereas Sandberg [62]in a review of his own and published variants concluded that the survival of CML cases with variant rearrangements was not significantly different from those with standard Ph translocation.…”

Section: Chromosome Banding Revealed Variant Translocations In CMLmentioning

confidence: 99%

Cytogenetic and Molecular Genetic Evolution of Chronic Myeloid Leukemia

2002

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Chronic myeloid leukemia (CML) is genetically characterized by the presence of the reciprocal translocation t(9;22)(q34;q11), resulting in a BCR/ABL gene fusion on the derivative chromosome 22 called the Philadelphia (Ph) chromosome. In 2–10% of the cases, this chimeric gene is generated by variant rearrangements, involving 9q34, 22q11, and one or several other genomic regions. All chromosomes have been described as participating in these variants, but there is a marked breakpoint clustering to chromosome bands 1p36, 3p21, 5q13, 6p21, 9q22, 11q13, 12p13, 17p13, 17q21, 17q25, 19q13, 21q22, 22q12, and 22q13. Despite their genetically complex nature, available data indicate that variant rearrangements do not confer any specific phenotypic or prognostic impact as compared to CML with a standard Ph chromosome. In most instances, the t(9;22), or a variant thereof, is the sole chromosomal anomaly during the chronic phase (CP) of the disease, whereas additional genetic changes are demonstrable in 60–80% of cases in blast crisis (BC). The secondary chromosomal aberrations are clearly nonrandom, with the most common chromosomal abnormalities being +8 (34% of cases with additional changes), +Ph (30%), i(17q) (20%), +19 (13%), –Y (8% of males), +21 (7%), +17 (5%), and monosomy 7 (5%). We suggest that all these aberrations, occurring in >5% of CML with secondary changes, should be denoted major route abnormalities. Chromosome segments often involved in structural rearrangements include 1q, 3q21, 3q26, 7p, 9p, 11q23, 12p13, 13q11–14, 17p11, 17q10, 21q22, and 22q10. No clear-cut differences as regards type and prevalence of additional aberrations seem to exist between CML with standard t(9;22) and CML with variants, except for slightly lower frequencies of the most common changes in the latter group. The temporal order of the secondary changes varies, but the preferred pathway appears to start with i(17q), followed by +8 and +Ph, and then +19. Molecular genetic abnormalities preceding, or occurring during, BC include overexpression of the BCR/ABL transcript, upregulation of the EVI1 gene, increased telomerase activity, and mutations of the tumor suppressor genes RB1, TP53, and CDKN2A. The cytogenetic evolution patterns vary significantly in relation to treatment given during CP. For example, +8 is more common after busulfan than hydroxyurea therapy, and the secondary changes seen after interferon-alpha treatment or bone marrow transplantation are often unusual, seemingly random, and occasionally transient. Apart from the strong phenotypic impact of addition of acute myeloid leukemia/myelodysplasia-associated translocations and inversions, such as inv(3)(q21q26), t(3;21)(q26;q22), and t(15;17)(q22;q12–21), in CML BC, only a few significant differences between myeloid and lymphoid BC are discerned, with i(17q) and TP53 mutations being more common in myeloid BC and monosomy 7, hypodiploidy, and CDKN2A deletions being more frequent in lymphoid BC. The prognostic significance of the secondary genetic changes is not uniform, althoug...

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The incidence, type, and subsequent evolution of 14 variant Ph1 translocations in 180 South African patients with Ph1-positive chronic myeloid leukemia

Cited by 40 publications

References 27 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

Variant Philadelphia translocations: molecular-cytogenetic characterization and prognostic influence on frontline imatinib therapy, a GIMEMA Working Party on CML analysis

Cytogenetic and Molecular Genetic Evolution of Chronic Myeloid Leukemia

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