Philadelphia-Chromosom

Philadelphia chromosome is the name given to the truncated chromosome number 22, which was formed by the reciprocal translocation t(9;22)(q34;q11).

In classical chronic myeloid leukemia, the translocation t(9;22)(q34;q11), occurs as a balanced reciprocal translocation . The truncated chromosome number 22 = Philadelphia chromosome shows a BCR gene rearrangement , which is caused by translocation of the c-ABL protooncogene from chromosome 9 to chromosome 22 into the region of the BCR gene (breakpoint cluster region). The translocation results in the formation of two fusion genes - the BCR/ABL1 fusion gene on the Philadelphia chromosome and the ABL1/BCR fusion gene on the elongated chromosome 9 q+.

The BCR/ABL1 fusion gene encodes the BCR/ABL1 fusion protein, which has constitutively active tyrosine kinase activity with proliferation-promoting and apoptosis-inhibiting effects.

The reciprocal translocation t(9;22)(q34;q11) with the corresponding Philadelphia chromosome is the diagnostic marker of chronic myeloid leukemia (CML) (Stam K et al 1985). In more than 90% of CML patients, the Philadelphia chromosome or the translocation t(9;22)(q34;q11) can be detected cytogenetically (Hochhaus A et al. 2013).

However, the translocation t(9;22)(q34;q11) is not pathognomonic for CML, but can also be detected in a proportion of adult and childhood acute lymphoblastic leukemias (ALL), as well as in a small proportion of acute myeloid leukemias (AML).

Furthermore, the translocation t(9;22)(q34;q11) is found in (rare) chronic neutrophil leukemia (CNL) , in lymphomas and in myelomas (van den Berghe H et al. 1979).

Different breakpoints exist that lead to the reciprocal translocation t(9;22)(q34;q11). Depending on where the breakpoints are located, different fusion genes and different fusion proteins are produced. The ABL1 gene has three common breakpoints: a breakpoint upstream of the first alternative exon 1b, a breakpoint between alternative exons 1b and 1a, and a breakpoint downstream of exon 1a.

The breakpoints of the BCR gene are usually located in one of three "breakpoint cluster regions".

A distinction is made here between a

• major breakpoint cluster region (M-BCR)
• a minor breakpoint cluster region (m-BCR) and
• a micro breakpoint cluster region (µ-BCR).

The major breakpoint cluster region (M-BCR) comprises the five exons e12-e16. In the M-BCR, we distinguish a breakpoint between e13 (b2) and e14 (b3), and a breakpoint between e14 (b3) and e15 (b4). The M-BCR) includes exons e1-e2, a breakpoint is located between the alternative exon e2' and exon e2. In case of a break event, the alternative exons e1' and e2'(not considered in the graphs) are removed by alternative splicing and only exon e1 and e2 participate in the fusions. The µ-BCR includes exons e17-e20, which were originally designated as exon c1-c4. In the µ-BCR, in addition to a breakpoint between e19 (c3) and e20 (c4), a breakpoint between e18 (c2) and e19 (c3) has also been described(Knas T 2016).

Furthermore, rare breakpoints such as between exon e6 and e7 or between exon e8 and e9 are known). Depending on where the respective breakpoints are located, different fusion proteins are generated.

The p210BCR/ABL1 fusion protein is formed by an e13a2 (b2a2) or an e14a2 (b3a2) fusion and has a molecular mass of 210 kDa. It is found in almost all CML patients, as well as in one third of ALL patients.

The p190BCR/ABL1 fusion protein results from the e1a2 fusion and measures 190 kDa. It is found in two-thirds of ALL patients and rarely in CML and AML patients.

The p230BCR/ABL1 fusion protein, on the other hand, results from the e19a2 (c3a2) fusion and has a molecular mass of 230 kDa. It is found in chronic neutrophil leukemia (CNL).

1. de Klein A et al.(1982) A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature 300: 765-767
2. Daley GQ et al (1990) Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247: 824-830
3. Davis RL et al (1985) Activation of the c-abl oncogene by viral transduction or chromosomal translocation generates altered c-abl proteins with similar in vitro kinase properties. Mol Cell Biol 5: 204-213
4. Hochhaus A et al (2013) Therapy of chronic myeloid leukemia - Open questions and possible solutions. Cancer Medicine 22: 79-86.
5. Knas T (2016) Detection of BCR/ABL1 fusion - Comparative analysis of six commercial probe sets for fluorescence in situ hybridization. Dissertation for the degree of Doctor of Medicine of the Medical Faculty of the University of Ulm, Germany.
6. Koretzky GA (2007) The legacy of the Philadelphia chromosome. J Clin Invest 117: 2030-2032
7. Stam K et al (1985) Evidence of a new chimeric bcr/c-abl mRNA in patients with chronic myelocytic leukemia and the Philadelphia chromosome. N Engl J Med 313: 1429- 1433
8. van den Berghe H et al (1979) Philadelphia chromosome in human multiple myeloma. J Natl Cancer Inst 63: 11-16