Heterogenic molecular basis for loss of ABL1‐BCR transcription: Deletions in der(9)t(9;22) and variants of standard t(9;22) in BCR‐ABL1‐positive chronic myeloid leukemia

Abstract

The objective of this study was to characterize the ABL1-BCR fusion gene in 76 BCR-ABL1-positive chronic myeloid leukemia (CML) patients regarding expression as well as genomic status, to assess the frequency of ABL1-BCR gene deletion in these patients, which has been reported to be an adverse prognostic factor in Philadelphia chromosome-positive CML. Patients were analyzed for ABL1-BCR 1b-b3 and/or 1b-b4 transcription by RT-PCR analysis. ABL1-BCR gene status was analyzed by FISH in 16 CML patients with no ABL1-BCR transcript. FISH revealed a partial or total deletion of the ABL1-BCR gene in 9/16 and localized the 5' portion of ABL1 and the 3' portion of BCR at separated loci in 5/16 patients. The latter FISH pattern resulted from a nonreciprocal translocation in two and a complex translocation in three individuals. In 2/16 patients, FISH could not exclude an intact ABL1-BCR fusion gene. Thus, most CML patients without ABL1-BCR transcript could be characterized cytogenetically to belong to two major subgroups: a silent ABL1-BCR gene was attributed to a deletion in der(9)t(9;22) in 56% of the investigated patients or to variants of a standard t(9;22) (approximately 31%). Conversely, none of the 50 patients with an ABL1-BCR transcript exhibited a variant t(9;22) in GTG-banding analysis. Thus, genomic aberrations such as deletions or complex genomic rearrangements are the basic and most frequent cause for ABL1-BCR RNA negativity in CML. The heterogeneity of the underlying molecular mechanisms may explain divergent clinical implications described for patients with an ABL1-BCR deletion and those with no ABL1-BCR transcript.

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

“…All patients who lacked an intact ABL/BCR signal, either via deletion or physical disruption of the loci, also lacked detectable expression of the fusion gene as demonstrated previously by ourselves and others (de la Fuente et al, 2001;Huntly et al, 2002;Loncarevic et al, 2002). In contrast, of three patients with fusion of 5¢ABL and 3¢BCR FISH signals tested by RT-PCR, only two were shown to express an ABL-BCR transcript, while in the remaining patient no expression was detected.…”

“…One such patient was recently reported by Loncarevic et al (2002). The authors speculated that the variant Ph rearrangement in this patient had occurred via two serial translocations, as four breaks must be necessary to maintain the integrity of ABL-BCR.…”

“…Reverse transcription polymerase chain reaction (RT-PCR) studies have recently revealed that the majority of variant Ph-positive CML patients lack expression of the reciprocal fusion gene ABL-BCR, usually present on the der(9) chromosome (Huntly et al, 2002;Loncarevic et al, 2002). In approximately half these patients, lack of ABL-BCR expression can be accounted for by the presence of a der(9) deletion.…”

“…In approximately half these patients, lack of ABL-BCR expression can be accounted for by the presence of a der(9) deletion. Abrogation of ABL-BCR in the remaining patients, however, has been shown by FISH to occur via physical separation of the 3¢ABL and 5¢BCR regions, as a result of the complex nature of the translocation (Markovic et al, 2000;Reid et al, 2001;Loncarevic et al, 2002). A small subset of variant Ph-positive patients has been shown to retain the ABL-BCR fusion (Reddy & Sulcova, 2000;Loncarevic et al, 2002), however, the exact frequency and significance of these findings has not been investigated.…”

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

“…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.…”