Rearrangement of the bcr gene in Philadelphia chromosome-negative chronic myeloid leukemia

Abstract

We studied the clinical, hematologic, cytogenetic, and molecular biologic features of seven patients with Philadelphia (Ph1) chromosome- negative chronic myeloid leukemia (CML). In five cases the hematologic findings were indistinguishable from those of patients with classical Ph1-positive disease. Myeloid cells were studied by chromosome-banding techniques. One patient had a masked Ph1 chromosome (with translocation t(4;9;22)), one had a deletion involving chromosome 16, and one had a small minority population of 22q- cells without 9q+ but otherwise normal metaphases; metaphases from the other four patients were entirely normal. DNA prepared from the myeloid cells was digested with the restriction enzymes EcoRI, HindIII, BamHI and BglII. Southern analysis using a 0.6-kb fragment of the breakpoint cluster region (bcr) gene showed the presence in each patient's DNA of a germline fragment together with a rearranged fragment or fragments with at least one of the restriction enzymes. We conclude that genomic changes in the bcr gene characteristic of CML can be present in the absence of a Ph1 chromosome.

A complex chromosome rearrangement forms the BCR‐ABL fusion gene in leukemic cells with a normal karyotype

“…Of particular interest is a small group of Ph'negative patients whose leukemic cells have no apparent cytogenetic abnormality, but that nevertheless show BCR-ABL association. This finding has been demonstrated in leukemic cells with apparently normal karyotypes from patients with Ph'negative chronic myeloid leukemia (CML) and essential thrombocythemia (ET) (Ganesan et al, 1986;Morris et al, 1986Morris et al, , 1988avan der Plas et al, 1989). It was shown recently that the apparently normal karyotypes of these patients do in fact conceal chromosome rearrangements: translocations in three patients (Inazawa et al, 1989;van der Plas et al, 1989) and either translocation or insertion in a fourth patient (Morris et al, 1990b).…”

Molecular and cytogenetic studies of a patient with philadelphia‐negative, BCR‐positive chronic myeloid leukemia and t(12;12)(q13;p12)

“…This raises the question of whether ABLIBCR fusion is responsible for CML development in these patients. Using Southern blot analysis, it is possible to demonstrate that half of these Ph'-negative patients carry a BCR rearrangement Bartram and Carbonell, 1986;Ganesan et al, 1986;Kurzock et al, 1986;Dreazen et al, 1987). This can be demonstrated because BCR rearrangements are clustered.…”

“…However, over half of the Ph'-negative CML patients studied have rearrangement of BCR. In some of these cases, it has also been possible to demonstrate the involvement of ABL, by in situ hybridization or production of a chimeric ABLIBCR mRNA Bartram and Carbonell, 1986;Ganesan et al, 1986;Kurzock et al, 1986;Dreazen et al, 1987). These findings indicate that Ph'-negative CML may be a heterogenous group, possibly with different pathogenetic pathways.…”

Oncogenes in Human Leukemias

“…This gene is transcribed into a chimeric RNA and into a fusion bcrlabf protein. It is usually possible to detect a rearrangement in bcr, even in cases of CML that lack the typical t(9;22) translocation [38][39][40][41]. A similar rearrangement is detected in some cases of ALL and AML with the Ph' chromosome and the t(9;22) translocation.…”

“…Several researchers, ourselves included, have indentified a novel 8 to [39,40], and in Ph' positive ALL with rearrangement of the bcr gene [42][43][44]. Abnormal c-abl expression has been reported in a B cell line derived from a patient with pre-B cell ALL [19].…”