Cytogenetics of Chronic Myeloid Leukemia (CML)

Abstract

Telling the story of the advances in chronic myeloid leukemia (CML), seen from a historical perspective, one cannot deny the extraordinary role of cytogenetics. When John Hughes Bennett and Rudolf Virchow reported what is thought to be the first descriptions of CML in 1845, nothing was known about the mechanism and the underlying genetics. Therefore, it was a quantum leap when the Philadelphia chromosome was discovered by Peter Nowel and David Hungerford in 1960 [1, 2]. By that time, they still used very basic chromosome staining techniques. The cells were grown on slides using short-term cell cultures [3], rinsed with tap water, and stained with Giemsa [4, 5]. Investigating acute leukemia they initially did not find consistent genetic abnormalities, but eventually they identified a characteristic small chromosome in two patients with CML. Together with other scientists like Paul Moorhead they were able to improve their preparation technique and report a series of seven patients all displaying a minute chromosome. In accordance with the Committee for the Standardization of Chromosomes, Tough and colleagues called this minute chromosome Philadelphia chromosome after the city it was first detected [4]. As cytogenetic techniques improved in the 1970s, Rowley discovered that the Philadelphia chromosome is the result of a translocation t(9;22)(q34;q11) between the long arms of chromosomes 9 and 22 with the derivative chromosome 22, der(22)t(9;22), being the Philadelphia chromosome [6]. de Klein et al. were then able to demonstrate that a small segment of chromosome 9 was translocated back to chromosome 22, providing evidence for the reciprocal nature of the translocation t(9;22) [7]. Later, Bartram and co-workers could show that the tyrosine kinase gene ABL1 (abelson) on chromosome 9 and the BCR (breakpoint cluster region) gene on chromosome 22 are fused and generate the BCR-ABL1 fusion gene on the Philadelphia chromosome [8–10]. This was the basis for the characterization of the BCR-ABL1 fusion protein, the development of the first BCR-ABL1 tyrosine kinase inhibitor (TKI) imatinib in 1996 and the success story of CML treatment [11–13]. Currently, the life expectancy of patients with newly diagnosed CML in chronic phase (CP) is very close to that of age-matched individuals [14, 15].