Translocation of BCR to chromosome 9: A new cytogenetic variant detected by FISH in two Ph‐negative, BCR‐positive patients with chronic myeloid leukemia

Abstract

Leukemic cells from two patients with Philadelphia-negative chronic myeloid leukemia (CML) were investigated: 1) Cytogenetics showed a normal 46,XY karyotype in both cases, 2) molecular studies revealed rearrangement of the M-BCR region and formation of BCR-ABL fusion mRNA with b2a2 (patient 1) or b3a2 (patient 2) configuration, and 3) fluorescence in situ hybridization (FISH) demonstrated relocation of the 5' BCR sequences from one chromosome 22 to one chromosome 9. The ABL probe hybridized to both chromosomes 9 at band q34, while two other probes which map centromeric and telomeric of BCR on 22q11 hybridized solely with chromosome 22. For the first time, a BCR-ABL rearrangement is shown to take place on 9q34 instead of in the usual location on 22q11. A rearrangement in the latter site is found in all Ph-positive CML and in almost all investigated CML with variant Ph or Ph-negative, BCR-positive cases. The few aberrant chromosomal localizations of BCR-ABL recombinant genes found previously were apparently the result of complex and successive changes. Furthermore in patient 2, both chromosomes 9 showed positive FISH signals with both ABL and BCR probes. Restriction fragment length polymorphism (RFLP) analysis indicated that mitotic recombination had occurred on the long arm of chromosome 9 and that the rearranged chromosome 9 was of paternal origin. The leukemic cells of this patient showed a duplication of the BCR-ABL gene, analogous to duplication of the Ph chromosome in classic CML. In addition they had lost the maternal alleles of the 9q34 chromosomal region.(ABSTRACT TRUNCATED AT 250 WORDS)

Atypical fluorescence in situ hybridisation pattern in chronic myeloid leukaemia due to cryptic insertion of BCR at 9q34

“…There are two points of note in the present case. First, for cryptic insertion of BCR at 9q34, both ours and several previously reported cases 3,6,7 showed normal chromosomes 9 and 22 (ie Ph chromosome negative). Therefore, in Ph-negative BCR/ ABL-positive CML, the absence of extra red signal on interphase ES-FISH and 1R2G1F pattern on interphase D-FISH should raise the possibility of cryptic insertion of BCR at 9q34.…”

“…This is in line with the previously published incidence of this pattern. 2,3 In most of these 15 cases (n ¼ 13; 7%), the presence of an extensive del(9q) was confirmed by metaphase analyses with both the ES and the D-FISH probes; all of them showed a typical Ph chromosome on conventional cytogenetics. In contrast, two patients (1%) had a normal karyotype with no Ph chromosome being detected; the BCR/ABL gene rearrangements observed in both cases were due to a cryptic insertion of BCR in 9q34, as confirmed by metaphase FISH.…”

“…In particular, the loss of one red signal in BCR/ABL dual colour extra signal (ES) probe system is found to be genetically heterogeneous, and may represent either derivative chromosome 9q deletions or cryptic insertion of BCR at 9q34. While the former aberration is well described, 2 the latter event is unusual 3 and has hitherto not been thoroughly evaluated using different readily available FISH probe systems. We present the atypical FISH patterns in a case of CML with BCR/ABL fusion on 9q as a result of cryptic insertion of BCR at 9q34, and discuss their interpretation.…”

t(7;12)(q36;p13) and t(7;12)(q32;p13) – translocations involving ETV6 in children 18 months of age or younger with myeloid disorders

“…Fixed chromosome suspensions from three Dutch patients were available for dual-color fluorescence in situ hybridization (FISH) analysis which was performed according to the method of Hagemeijer et al 5 We used ETV6 cosmid probes that spanned most of the gene from exon 1 to exon 8 (tel-179A6 -15A4 -50F4 -132B11 -54D5 -cen), 3 and subtelomeric probes specific for 7q (2000a5) and for 12p (9015). 6 Also available as probes in this study were a cosmid that contained the entire ENOS gene at 7q36 and 4.5-kb sequences that flanked this gene; 7 the CEPH YAC 965FCF12 (locus D7S550; size 160 kb), which is also localized to 7q36; and an alpha satellite probe for the centromeric region of chromosome 7 (p7t1).…”

Chronic myeloid leukaemia with BCR–ABL fusion genes located to both chromosomes 9, cyclic leukocytosis and nodal T-lymphoblastic transformation – durable complete remission following imatinib therapy

“…5 Of special interest, the reported patient had two BCR-ABL fusion genes in each cell located at 9q34. Five similar Phnegative cases with double BCR-ABL fusion genes have been published previously; 6-9 three were in chronic phase, 6,8 two were in myeloid blast crisis. 7,9 The described variant Phtranslocation could be the result of either an insertion of the 5 0 part of the BCR gene within or at the 5 0 side of the ABL gene on chromosome 9 or by two successive translocations, a classic t(9;22) followed by a second translocation between both derivatives 9q þ and 22qÀ, masking the first chromosomal exchange.…”