Philadelphia chromosome

The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short because of reciprocal translocation, t(9;22)(q34;q11), of genetic material between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1. This gene is the ABL1 gene of chromosome 9 juxtaposed onto the breakpoint cluster region BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signalling protein that is 'always on', causing the cell to divide uncontrollably by interrupting the stability of the genome and impairing various signaling pathways governing the cell cycle. The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short because of reciprocal translocation, t(9;22)(q34;q11), of genetic material between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1. This gene is the ABL1 gene of chromosome 9 juxtaposed onto the breakpoint cluster region BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signalling protein that is 'always on', causing the cell to divide uncontrollably by interrupting the stability of the genome and impairing various signaling pathways governing the cell cycle. The presence of this translocation is a highly sensitive test for CML, since all cases of CML are positive for BCR-ABL1. (Some cases are confounded by either a cryptic translocation that is invisible on G-banded chromosome preparations, or a variant translocation involving another chromosome or chromosomes as well as the long arm of chromosomes 9 and 22. Other similar but truly Ph-negative conditions are considered CML-like myeloproliferative neoplasms.) However, the presence of the Philadelphia (Ph) chromosome is not sufficiently specific to diagnose CML, since it is also found in acute lymphoblastic leukemia (aka ALL, 25–30% of adult cases and 2–10% of pediatric cases) and occasionally in acute myelogenous leukemia (AML) as well as mixed-phenotype acute leukemia (MPAL). The chromosomal defect in the Philadelphia chromosome is a reciprocal translocation, in which parts of two chromosomes, 9 and 22, swap places. The result is that a fusion gene is created by juxtaposing the ABL1 gene on chromosome 9 (region q34) to a part of the BCR (breakpoint cluster region) gene on chromosome 22 (region q11). This is a reciprocal translocation, creating an elongated chromosome 9 (termed a derivative chromosome, or der 9), and a truncated chromosome 22 (the Philadelphia chromosome, 22q-). In agreement with the International System for Human Cytogenetic Nomenclature (ISCN), this chromosomal translocation is designated as t(9;22)(q34;q11). The symbol ABL is derived from Abelson, the name of a leukemia virus which carries a similar protein. The symbol BCR is derived from breakpoint cluster region, a gene which encodes a protein that acts as a guanine nucleotide exchange factor for Rho GTPase proteins. Translocation results in an oncogenic BCR-ABL gene fusion that can be found on the shorter derivative 22 chromosome. This gene encodes for a BCR-ABL fusion protein. Depending on the precise location of fusion, the molecular weight of this protein can range from 185 to 210 kDa. Consequently, the hybrid BCR-ABL fusion protein is referred to as p210 or p185. Three clinically important variants encoded by the fusion gene are the p190, p210, and p230 isoforms. p190 is generally associated with B-cell acute lymphoblastic leukemia (ALL), while p210 is generally associated with chronic myeloid leukemia but can also be associated with ALL and AML. p230 is usually associated with chronic myelogenous leukemia associated with neutrophilia and thrombocytosis (CML-N). Additionally, the p190 isoform can also be expressed as a splice variant of p210. The Abl gene expresses a membrane-associated protein, a tyrosine kinase, and the BCR-Abl transcript is also translated into a tyrosine kinase containing domains from both the BCR and ABL1 genes. The activity of tyrosine kinases is typically regulated in an auto-inhibitory fashion, but the BCR-Abl fusion gene codes for a protein that is 'always on' or constitutively activated, leading to impaired DNA binding and unregulated cell division (i.e. cancer). This is due to the replacement of the myristoylated cap region, which when present induces a conformational change rendering the kinase domain inactive, with a truncated portion of the BCR protein. Although the BCR region also expresses serine/threonine kinases, the tyrosine kinase function is very relevant for drug therapy. As the N-terminal Y177 and CC domains from BCR encode the constitutive activation of the ABL1 kinase, these regions are targeted in therapies to downregulate BCR-ABL kinase activity. Tyrosine kinase inhibitors specific to such domains as CC, Y177, and Rho (such as imatinib and sunitinib) are important drugs against a variety of cancers including CML, renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GISTs). The fused BCR-ABL protein interacts with the interleukin-3 receptor beta(c) subunit and is moderated by an activation loop within its SH1 domain, which is turned “on” when bound to ATP and triggers downstream pathways. The ABL tyrosine kinase activity of BCR-Abl is elevated relative to wild-type ABL. Since ABL activates a number of cell cycle-controlling proteins and enzymes, the result of the BCR-Abl fusion is to speed up cell division. Moreover, it inhibits DNA repair, causing genomic instability and potentially causing the feared blast crisis in CML.