Philadelphia chromosome

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Philadelphia chromosome
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A metaphase cell positive for the bcr/abl rearrangement using FISH
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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 signaling 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. [1]

Contents

The presence of this translocation is required for diagnosis of CML; in other words, all cases of CML are positive for BCR-ABL1. [2] (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. [3] ) However, the presence of the Philadelphia (Ph) chromosome is not sufficiently specific to diagnose CML, since it is also found in acute lymphoblastic leukemia [4] (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).

Molecular biology

Schematic of the Philadelphia chromosome formation Schematic of the Philadelphia Chromosome.svg
Schematic of the Philadelphia chromosome formation

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-). [5] [6] In agreement with the International System for Human Cytogenetic Nomenclature (ISCN), this chromosomal translocation is designated as t(9;22)(q34;q11). The symbol ABL1 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. [7]

Translocation results in an oncogenic BCR-ABL1 gene fusion that can be found on the shorter derivative chromosome 22. This gene encodes for a BCR-ABL1 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-ABL1 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. [8] 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. [9] p230 is usually associated with chronic myelogenous leukemia associated with neutrophilia and thrombocytosis (CML-N). [9] Additionally, the p190 isoform can also be expressed as a splice variant of p210. [10]

The ABL1 gene expresses a membrane-associated protein, a tyrosine kinase, and the BCR-ABL1 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-ABL1 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. [11] 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-ABL1 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-ABL1 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 ABL1 tyrosine kinase activity of BCR-ABL1 is elevated relative to wild-type ABL1. [12] Since ABL activates a number of cell cycle-controlling proteins and enzymes, the result of the BCR-ABL1 fusion is to speed up cell division. Moreover, it inhibits DNA repair, causing genomic instability and potentially causing the feared blast crisis in CML.

Proliferative roles in leukemia

The BCR-ABL1 fusion gene and protein encoded by the Philadelphia chromosome affects multiple signaling pathways that directly affect apoptotic potential, cell division rates, and different stages of the cell cycle to achieve unchecked proliferation characteristic of CML and ALL.

JAK/STAT pathway

Particularly vital to the survival and proliferation of myelogenous leukemia cells in the microenvironment of the bone marrow is cytokine and growth factor signaling. The JAK/STAT pathway moderates many of these effectors by activating STATs, which are transcription factors with the ability to modulate cytokine receptors and growth factors. JAK2 phosphorylates the BCR-ABL fusion protein at Y177 and stabilizes the fusion protein, strengthening tumorigenic cell signaling. JAK2 mutations have been shown to be central to myeloproliferative neoplasms and JAK kinases play a central role in driving hematologic malignancies (JAK blood journal). ALL and CML therapies have targeted JAK2 as well as BCR-ABL using nilotinib and ruxolitinib within murine models to downregulate downstream cytokine signaling by silencing STAT3 and STAT5 transcription activation (appelmann et al.). The interaction between JAK2 and BCR-ABL within these hematopoietic malignancies implies an important role of JAK-STAT-mediated cytokine signaling in promoting the growth of leukemic cells exhibiting the Ph chromosome and BCR-ABL tyrosine kinase activity. Though the centrality of the JAK2 pathway to direct proliferation in CML has been debated, its role as a downstream effector of the BCR-ABL tyrosine kinase has been maintained. Impacts on the cell cycle via JAK-STAT are largely peripheral, but by directly impacting the maintenance of the hematopoietic niche and its surrounding microenvironment, the BCR-ABL upregulation of JAK-STAT signaling plays an important role in maintaining leukemic cell growth and division. [13] [14]

Ras/MAPK/ERK pathway

The Ras/MAPK/ERK pathway relays signals to nuclear transcription factors and plays a role in governing cell cycle control and differentiation. In Ph chromosome-containing cells, the BCR-ABL tyrosine kinase activates the RAS/RAF/MEK/ERK pathway, which results in unregulated cell proliferation via gene transcription in the nucleus. The BCR-ABL tyrosine kinase activates Ras via phosphorylation of the GAB2 protein, which is dependent on BCR-located phosphorylation of Y177. Ras in particular is shown to be an important downstream target of BCR-ABL1 in CML, as Ras mutants in murine models disrupt the development of CML associated with the BCR-ABL1 gene (Effect of Ras inhibition in hematopoiesis and BCR/ABL leukemogenesis). The Ras/RAF/MEK/ERK pathway is also implicated in overexpression of osteopontin (OPN), which is important for maintenance of the hematopoietic stem cell niche, which indirectly influences unchecked proliferation characteristic of leukemic cells. [15] BCR-ABL fusion cells also exhibit constitutively high levels of activated Ras bound to GTP, activating a Ras-dependent signaling pathway which has been shown to inhibit apoptosis downstream of BCR-ABL (Cortez et al.). Interactions with the IL-3 receptor also induce the Ras/RAF/MEK/ERK pathway to phosphorylate transcription factors which play a role in driving the G1/S transition of the cell cycle. [16] [17] [18]

DNA binding and apoptosis

The c-Abl gene in wild-type cells is implicated in DNA binding, which affects such processes as DNA transcription, repair, apoptosis, and other processes underlying the cell cycle. While the nature of this interaction has been debated, evidence exists to suggest that c-Abl phosphorylates HIPK2, a serine/threonine kinase, in response to DNA damage and promotes apoptosis in normal cells. The BCR-ABL fusion, in contrast, has been shown to inhibit apoptosis, but its effect on DNA binding in particular is unclear. [19] In apoptotic inhibition, BCR-ABL cells have been shown to be resistant to drug-induced apoptosis but also have a proapoptotic expression profile by increased expression levels of p53, p21, and Bax. The function of these pro-apoptotic proteins, however, is impaired, and apoptosis is not carried out in these cells. BCR-ABL has also been implicated in preventing caspase 9 and caspase 3 processing, which adds to the inhibitory effect. [20] [21] Another factor preventing cell cycle progression and apoptosis is the deletion of the IKAROS gene, which presents in >80% of Ph chromosome–positive ALL cases. The IKAROS gene is critical to pre-B cell receptor–mediated cell cycle arrest in ALL cells positive for Ph, which when impaired provides a mechanism for unchecked cell cycle progression and proliferation of defective cells as encouraged by BCR-ABL tyrosine kinase signaling. [22]

Nomenclature

The Philadelphia chromosome is designated Ph (or Ph') chromosome and designates the shortened chromosome 22 which encodes the BCR-ABL fusion gene/protein kinase. It arises from the translocation, which is termed t(9;22)(q34.1;q11.2), between chromosome 9 and chromosome 22, with breaks happening in region (3), band (4), sub-band (1) of the long arm (q) of chromosome 9 and region (1), band (1), sub-band (2) of the long arm (q) of chromosome 22. Hence the chromosome breakpoints are written as (9q34.1) and (22q11.2), respectively, using ISCN standards.

Therapy

Tyrosine kinase inhibitors

Crystal structure of Abl kinase domain (blue) in complex with 2nd generation tyrosine kinase inhibitor (TKI) nilotinib (red) 3CS9 Abl1 Nilotinib.png
Crystal structure of Abl kinase domain (blue) in complex with 2nd generation tyrosine kinase inhibitor (TKI) nilotinib (red)

In the late 1990s, STI-571 (imatinib, Gleevec/Glivec) was identified by the pharmaceutical company Novartis (then known as Ciba Geigy) in high-throughput screens for tyrosine kinase inhibitors. Subsequent clinical trials led by Dr. Brian J. Druker at Oregon Health & Science University in collaboration with Dr. Charles Sawyers and Dr. Moshe Talpaz demonstrated that STI-571 inhibits proliferation of BCR-ABL-expressing hematopoietic cells. Although it did not eradicate CML cells, it did greatly limit the growth of the tumor clone and decreased the risk of the feared "blast crisis".[ citation needed ] In 2000 Dr. John Kuriyan determined the mechanism by which STI-571 inhibits the Abl kinase domain. [23] It was marketed in 2001 by Novartis as imatinib mesylate (Gleevec in the US, Glivec in Europe).

Other pharmacological inhibitors are being developed, which are more potent and/or are active against the emerging Gleevec/Glivec resistant BCR-abl clones in treated patients. The majority of these resistant clones are point-mutations in the kinase of BCR-abl. New inhibitors include dasatinib and nilotinib, which are significantly more potent than imatinib and may overcome resistance. Combination therapies with nilotinib and ruxolitnib have also shown success in suppressing resistance by targeting the JAK-STAT and BCR-ABL stages simultaneously. Small molecule inhibitors, like arsenic trioxide and geldanamycin analogues, have also been identified in downregulating BCR-ABL kinase translation and promoting its degradation by protease. [24] [25]

Axitinib, a drug used to treat renal cell carcinoma, has been shown to be effective at inhibiting the Abl kinase activity in patients with BCR-ABL1(T315I). [26] The T315I mutation in the fusion gene confers resistance to other tyrosine kinase inhibitors such as imatinib, however axitinib has been successfully been used to treat a patient with ALL carrying this mutation, as well as CML cells in culture.

Treatment of pediatric Ph+ ALL with a combination of standard chemotherapy and RTK inhibitors may result in remission,[ citation needed ] but the curative potential is unknown.

Asciminib (Scemblix) was approved for medical use in the United States in October 2021. [27]

Blood or marrow transplants

A potentially curative, but risky, option for pediatric Ph+ ALL or Ph+ CML is bone marrow transplant or cord blood transplant, but chemotherapy is favored by some for achieving first remission (CR1). For some, bone marrow transplant from a matched sibling donor or a matched, unrelated donor may be favored when remission is obtained.

Cord blood transplant is favored by some when a 10/10 bone marrow match is not available, and cord blood transplant may have some advantages, including a reduced incidence of graft-vs-host disease (GVHD), which is a common and significant complication of transplant. However, transplant with cord blood sometimes requires longer periods of time for engraftment, which may increase the potential for complications due to infection. Regardless of the type of transplant, transplant-related mortality and relapse are possible, and the rates may change as treatment protocols improve. For second remission (CR2), if achieved, both chemotherapy and transplant options are possible, and many physicians prefer transplant.[ citation needed ]

Prognosis

BCR-ABL positive acute lymphoblastic leukemia (ALL) has a 5-year survival rate ranging from 50% to 75%, in studies of the era of tyrosine kinase inhibitors. [28]

History

The Philadelphia chromosome was first discovered and described in 1959 by David Hungerford at the Lankenau Hospital's Institute for Cancer Research, which merged with the American Oncology Hospital in 1974 to create Fox Chase Cancer Center, [29] along with Peter Nowell from the University of Pennsylvania School of Medicine. The genetic abnormality Hungerford and Nowell found was named after the city in which both organizations were located. [1] [30] [29] [31] And thus, this is a typical example of a medical toponym.

Hungerford was writing his doctoral thesis on chromosomes in a genetics lab at what was then the Institute for Cancer Research at the Lankenau Hospital Research Institute, [29] and detected a flaw in chromosomes from the blood cells of patients with leukemia. This founding observation was the first genetic defect to be linked with a specific human cancer. Nowell was a pathologist at the University of Pennsylvania who was also studying leukemia cells under the microscope when he noticed cells with this genetic flaw in the act of dividing. To his surprise, their chromosomes—usually an indistinct tangle—were visible as separate structures. In searching for an expert on chromosomes, Nowell found Hungerford locally at Lankenau. While conducting his microscopic studies, Hungerford furthered his observations with the discovery that certain leukemia cells had an abnormally short chromosome 22. Subsequently, the mutation he observed became known as the Philadelphia chromosome.

In 1973, Janet Rowley at the University of Chicago identified the mechanism by which the Philadelphia chromosome arises as a translocation. [1] [32] [33]

See also

Related Research Articles

<span class="mw-page-title-main">Oncogene</span> Gene that has the potential to cause cancer

An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

<span class="mw-page-title-main">Tyrosine kinase</span> Class hi residues

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.

<span class="mw-page-title-main">Chronic myelogenous leukemia</span> Medical condition

Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes and their precursors is found; characteristic increase in basophils is clinically relevant. It is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation called the Philadelphia chromosome.

<span class="mw-page-title-main">Imatinib</span> Chemical compound

Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral targeted therapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple tyrosine kinases such as CSF1R, ABL, c-KIT, FLT3, and PDGFR-β. Specifically, it is used for chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) that are Philadelphia chromosome–positive (Ph+), certain types of gastrointestinal stromal tumors (GIST), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), systemic mastocytosis, and myelodysplastic syndrome.

<span class="mw-page-title-main">ABL (gene)</span> Human protein-coding gene on chromosome 9

Tyrosine-protein kinase ABL1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammalian genome, while v-Abl refers to the viral gene, which was initially isolated from the Abelson murine leukemia virus.

K562 cells were the first human immortalised myelogenous leukemia cell line to be established. K562 cells are of the erythroleukemia type, and the cell line is derived from a 53-year-old female chronic myelogenous leukemia patient in blast crisis. The cells are non-adherent and rounded, are positive for the bcr:abl fusion gene, and bear some proteomic resemblance to both undifferentiated granulocytes and erythrocytes.

<span class="mw-page-title-main">Dasatinib</span> Chemical compound

Dasatinib, sold under the brand name Sprycel among others, is a targeted therapy medication used to treat certain cases of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Specifically it is used to treat cases that are Philadelphia chromosome-positive (Ph+). It is taken by mouth.

<span class="mw-page-title-main">BCR (gene)</span>

The breakpoint cluster region protein (BCR) also known as renal carcinoma antigen NY-REN-26 is a protein that in humans is encoded by the BCR gene. BCR is one of the two genes in the BCR-ABL fusion protein, which is associated with the Philadelphia chromosome. Two transcript variants encoding different isoforms have been found for this gene.

<span class="mw-page-title-main">CCL9</span> Mammalian protein found in Mus musculus

Chemokine ligand 9 (CCL9) is a small cytokine belonging to the CC chemokine family. It is also called macrophage inflammatory protein-1 gamma (MIP-1γ), macrophage inflammatory protein-related protein-2 (MRP-2) and CCF18, that has been described in rodents. CCL9 has also been previously designated CCL10, although this name is no longer in use. It is secreted by follicle-associated epithelium (FAE) such as that found around Peyer's patches, and attracts dendritic cells that possess the cell surface molecule CD11b and the chemokine receptor CCR1. CCL9 can activate osteoclasts through its receptor CCR1 suggesting an important role for CCL9 in bone resorption. CCL9 is constitutively expressed in macrophages and myeloid cells. The gene for CCL9 is located on chromosome 11 in mice.

<span class="mw-page-title-main">STAT5</span> Protein family

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<span class="mw-page-title-main">Acute myeloblastic leukemia with maturation</span> Medical condition

Acute myeloblastic leukemia with maturation (M2) is a subtype of acute myeloid leukemia (AML).

<span class="mw-page-title-main">ETV6</span> Protein-coding gene in the species Homo sapiens

ETV6 protein is a transcription factor that in humans is encoded by the ETV6 gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those of hematological tissues. However, its gene, ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e., ETV6 is a clinically significant proto-oncogene in that it can fuse with other genes to drive the development and/or progression of certain cancers. However, ETV6 is also an anti-oncogene or tumor suppressor gene in that mutations in it that encode for a truncated and therefore inactive protein are also associated with certain types of cancers.

<span class="mw-page-title-main">PDGFRB</span> Protein-coding gene in the species Homo sapiens

Platelet-derived growth factor receptor beta is a protein that in humans is encoded by the PDGFRB gene. Mutations in PDGFRB are mainly associated with the clonal eosinophilia class of malignancies.

<span class="mw-page-title-main">DOK1</span> Protein-coding gene in the species Homo sapiens

Docking protein 1 is a protein that in humans is encoded by the DOK1 gene.

<span class="mw-page-title-main">Bosutinib</span> Chemical compound

Bosutinib, sold under the brand name Bosulif, is a small molecule BCR-ABL and src tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia.

Bcr-Abl tyrosine-kinase inhibitors (TKI) are the first-line therapy for most patients with chronic myelogenous leukemia (CML). More than 90% of CML cases are caused by a chromosomal abnormality that results in the formation of a so-called Philadelphia chromosome. This abnormality was discovered by Peter Nowell in 1960 and is a consequence of fusion between the Abelson (Abl) tyrosine kinase gene at chromosome 9 and the break point cluster (Bcr) gene at chromosome 22, resulting in a chimeric oncogene (Bcr-Abl) and a constitutively active Bcr-Abl tyrosine kinase that has been implicated in the pathogenesis of CML. Compounds have been developed to selectively inhibit the tyrosine kinase.

<span class="mw-page-title-main">Ponatinib</span> Oral drug

Ponatinib, sold under the brand name Iclusig, is a medication developed by ARIAD Pharmaceuticals for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). It is a multi-targeted tyrosine-kinase inhibitor. Some forms of CML, those that have the T315I mutation, are resistant to current therapies such as imatinib. Ponatinib has been designed to be effective against these types of tumors.

Atypical chronic myeloid leukemia (aCML) is a type of leukemia. It is a heterogeneous disorder belonging to the group of myelodysplastic/myeloproliferative (MDS/MPN) syndromes.

Clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell that occupies the bone marrow, blood, and other tissues. This population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell.

<span class="mw-page-title-main">Asciminib</span> Chemical compound

Asciminib, sold under the brand name Scemblix, is a medication used to treat Philadelphia chromosome-positive chronic myeloid leukemia. Asciminib is a protein kinase inhibitor.

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