Non-random involvement of chromosome 13 in patients with persistent or relapsed disease after bone-marrow transplantation for chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) patients with persistent or relapsed disease following bone-marrow transplantation (BMT) usually show both clonal and non-clonal cytogenetic changes in addition to the Philadelphia (Ph) translocation. These changes are presumably due to conditioning prior to transplantation and are generally not thought to be of clinical significance. We have examined the additional cytogenetic changes found in Ph+ve cells after BMT in 47 CML patients. Forty patients showed clonal changes. The involvement of each chromosome was compared statistically with expected values assuming that further chromosome changes are random and related to chromosome size. In clones that comprised 50% or more of the Ph+ve metaphases, chromosome 13 was involved in 12 of 22 clones (55%); this was highly significant when compared with the theoretical expected value of 3.2 (14.5%) (P < 0.001). The chromosome 13 rearrangements comprised both translocations and deletions. By means of FISH with a panel of 13q YAC clones, the breakpoints in 6 of these patients were investigated, but no common site of translocation was identified. The YAC panel was then used on material from 6 patients with chromosomal deletions. A common region of deletion was identified at 13q12-14, suggesting the presence of one or more tumor suppressor genes. We conclude that chromosome 13 deletions are non-randomly overrepresented in Ph+ve metaphases following BMT for CML. Genes Chromosomes Cancer 27:278-284, 2000.

Cytogenetic evolution patterns in CML post-SCT

“…26 Some of the presently identified breakprone regions (1q21, 1q32, 7q22, 9q34, 11q13, 11q23, 12q24, 13q14, 17q10, and 22q11) are similar to the previously reported ones, in particular the clustering of chromosome 1 breaks and the frequent involvement of 13q14 (Figure 1), although it should be stressed that most of the cases in the previous studies also were included in the present literature review. Considering that Chase et al 26 reported quite a high frequency of 13q14 abnormalities but that we only had one such case, we used FISH to investigate whether 13q14 changes had been overlooked in our material. However, we found no evidence for 'cryptic' 13q14 aberrations.…”

“…2,[18][19][20][21][22][23] It has been suggested that these unusual abnormalities are caused by the conditioning regime, that is, occur as a consequence of the clastogenic effect of TBI and/or alkylating agents, most commonly CY. [21][22][23][24][25][26] Although this may well be true, one could also postulate that the emergence of 'unconventional' cytogenetic evolution is facilitated -or even caused -by the altered BM environment, that is, the presence of donor cells and/or the immunosuppression post-allo-SCT. If so, one would suspect that the karyotypic patterns would be different after allo-and autologous (auto)-SCT, which have similar conditioning regimes.…”

“…28 As Chase et al 26 reported a high frequency of 13q abnormalities, most often involving 13q12-14, in CMLs after allo-SCT we also specifically looked for such changes using fluorescence in situ hybridization (FISH) in nine cases where sufficient material was available for analysis. The following probes were used: LSI 13 for RB1 at 13q14 (Abbott, Stockholm, Sweden), BCR/ABL1 dual color, dual fusion (Abbott, Stockholm, Sweden), and RP11-310D8 (BACPAC Resources, Children's Hospital Oakland Research Institute, Oakland, CA, USA) mapping to distal 13q.…”

“…Then, all cases displaying either secondary changes in addition to t (9;22) or cytogenetically abnormal, but Ph chromosome-negative, clones after SCT were identified. Of the 115 cases found, 109 had undergone allo 2,12,[18][19][20][22][23][24][25][26] and six auto-SCT. 7,12,50,[52][53][54] The conditioning regime included TBI and/ or an alkylating agent in all (100%) of the 101 cases for which such data were available.…”

Similar patterns of chromosome abnormalities in CML occur in addition to the Philadelphia chromosome with or without tyrosine kinase inhibitor treatment

“…In the study of Karrman et al, 7 there was a lower frequency of major route abnormalities in recipients of allogeneic SCT (15%) when compared with those patients having received an autologous SCT (two from three patients with Ph þ clones). Chase et al 8 reported a high frequency of translocations and deletions involving 13q in recipients of allo-SCT who showed relapse or persistent disease. Therefore, allo-SCT seems to alter the biology in the Ph þ clones in patients with relapsing or persistent CML, whereas TKIs have no such effect and do not interfere with the pathways of Ph þ clonal evolution.…”