Heteromorphisms of the Philadelphia (Ph¹) Chromosome in Patients with Chronic Myelogenous Leukaemia (CML). I. CLASSIFICATION AND CLINICAL SIGNIFICANCE

Abstract

In patients with chronic myelogenous leukaemia (CML), we have found the break points on the long arm of chromosome 22 (22q) are variable (heteromorphic or polymorphic). Consequently, the Philadelphia (Ph1) chromosome is heteromorphic in size for the long arm. Based upon the break points and the relative size of chromosome 22, four types of Ph1 chromosomes are proposed. They are: Types I (very large), II (large), III (average) and IV (small) with the break points at bands 22q13.3, 22q13.1, 22q12 and 22q11.3, respectively. The break points are arbitrary and should not be considered absolute since they are based on length differences. In two cases the Ph1 chromosome involved a translocation between chromosome 9 and 22, and the other two cases chromosome 1 or 12. Because Types I and II are hard to recognize by conventional techniques, the RFA technique (R. band by fluorescence with acridine orange) must be performed on all cases. An earlier contention that only chromosome 22 band 12 is concerned with abnormal myeloid cell proliferation in human leukaemia is rejected. Furthermore, break points are not restricted at the junction of 22ql and q2 and 22q2 and q3 and can happen anywhere on the long arm of chromosome 22.

Spatial relationship of chromosomes 9 and 22 at metaphase in patients with chronic myelogenous leukemia (CML)

“…This observation is consistent with the long-accepted fact that acrocentric chromosomes (13-15, 21 and 22) show somatic association. CML represents an interesting situation among human cancers in that a specific chromosome abnormality involving chromosomes 9q and 22q is found in more than 96% of the patients (Verma and Dosik, 1980). In the typical cases of CML with the t(9;22), there has been considerable controversy whether the primary event is the transfer of genetic material from chromosome 9 to 22, or from chromosome 22 to 9.…”

High resolution breakpoints of the Philadelphia translocation in patients with chronic myelogenous leukemia

“…Several investigators reported the variety in the size of the Ph chromosome (Watt et al, 1977;Verma and Dosik, 1980). They suggested that the breakpoint may not be specific but can happen anywhere on chromosome //22.…”

“…They suggested that the breakpoint may not be specific but can happen anywhere on chromosome //22. Verma and Dosik (1980) described four different types of the Ph according to the size; small, average, large, and very large. However, their very large and large Ph chromosomes were derived from a variant translocation involving //22 and other chromosomes than//9.…”

“…In association with this translocation one of proto-oncogenes, c-abl, is translocated from chromosome #9 to //22 (Klein et al, 1982;Hagemeijer et al, 1984). Interestingly, several investigators have shown the variety in the size of the Ph chromosome by banding chromosome analysis (Watt et al, 1977;Verma and Dosik, 1980), which means the breakpoint may differ among different cases. We attempted to specify the breakpoints of the Ph translocation with elongated and finely banded chromosomes.…”