Chronic myeloid leukemia and genetics
Chronic myeloid leukemia (CML) is a type of cancer that affects the blood and bone marrow, characterized by the production of abnormal white blood cells. This disease typically progresses slowly over several years and can eventually transform into a more aggressive form known as acute myeloid leukemia (AML). A significant genetic feature of CML is the presence of the Philadelphia chromosome, resulting from a specific chromosomal rearrangement (the t(9;22) translocation). This genetic alteration leads to the formation of the BCR-ABL fusion gene, which produces a tyrosine kinase protein that contributes to uncontrolled cell growth.
CML is not inherited and arises from acquired mutations in adult life, primarily affecting middle-aged males. Risk factors include exposure to radiation and smoking, though the connection with lifestyle factors remains unclear. Symptoms can vary widely, including fatigue, unexplained weight loss, and bone pain, and require medical evaluation for accurate diagnosis. Treatment options have evolved, with targeted therapies such as imatinib and dasatinib becoming standard, replacing traditional chemotherapy in early-stage cases. The prognosis for CML is generally favorable, with a ten-year survival rate of about 85% for the most common form of the disease.
Chronic myeloid leukemia and genetics
ALSO KNOWN AS: Chronic myelocytic leukemia; CML; chronic myelogenous leukemia; chronic granulocytic leukemia
DEFINITION Chronic myeloid leukemia (CML) is a cancer of the blood and bone marrow. With CML, the bone marrow makes abnormal blood cells, including myeloblasts, a type of white blood cell that fights infection; red blood cells (RBCs) that carry oxygen; and platelets, which make blood clot and stop bleeding in cuts or bruises.
CML progresses gradually. It is often slow growing for many years. Eventually, it may transform itself into acute myeloid leukemia (AML). This is a more aggressive type of leukemia; it progresses much more rapidly and is more serious. Cancer occurs when cells in the body become abnormal. They divide without control or order. Leukemia is cancer of the white blood cells and their parent cells. Leukemia cells do not function normally; they cannot do what normal blood cells do. In this case they cannot fight infections, which means that the patient is more likely to become infected with viruses or bacteria. The cancerous cells also overgrow the bone marrow. This forces out other normal components, like platelets. Platelets are needed to help the blood clot. As a result, patients with leukemia may bleed more easily.
Risk Factors
Males and individuals who are middle-aged or older are at risk of developing CML. Other risk factors include exposure to atomic bomb radiation, exposure to a nuclear reactor accident, and smoking. Smoking is the only lifestyle factor that has been linked to leukemia, and its association with CML is still unclear. According to the National Cancer Institute, the prevalence rate for CML in the United States was about 1 in 526 people. Most cases are diagnosed in people over age 65.
Etiology and Genetics
Chronic myeloid leukemia is not an inherited disease, and it is not passed from parent to child. Yet it has a very characteristic and well understood genetic basis. It results from an acquired mutation, a mutational event that occurs usually in one's adult life and that involves only blood stem cells and white blood cells. It is generally diagnosed in cytogenetic studies by the appearance of a specific chromosomal rearrangement that results in a perceptibly shorter chromosome 22, known as the Philadelphia chromosome, named after the city in which it was first discovered. Segments of the long arms of chromosomes 9 and 22 break off, and they reattach to the wrong chromosome, yielding two translocated or hybrid chromosomes. The break on chromosome 22 occurs at the BCR locus (breakpoint cluster region), while chromosome 9 is cleaved in the middle of the ABL (Abelson leukemia virus) gene. One of the fusion products results in a new gene, BCR-ABL, that is expressed on chromosome 22. This hybrid gene encodes a protein with tyrosine activity, and it is the overexpression of tyrosine kinase in these blood stem cells which activates certain pathways and leads to uncontrolled cell growth. All of the resulting cells will have the Philadelphia chromosome, and this can be detected in a simple blood test.
Symptoms
Symptoms of CML may also be caused by other, less serious health conditions. A patient should see a doctor if he or she has any of the following symptoms: tiredness, lack of energy, fatigue, unexplained weight loss, night sweats, fever, pain or a feeling of fullness below the ribs, bone pain, joint pain, reduced exercise tolerance, enlargement of the liver or spleen, and unexplained bleeding or unusual bruising.
Screening and Diagnosis
The doctor will ask about a patient’s symptoms and medical history and will conduct a physical exam. The doctor will look for swelling of the liver or the spleen, as well as swelling in lymph nodes in the armpits, groin, or neck. A patient will likely be referred to an oncologist, a doctor who focuses on treating cancer.
Tests may include blood tests to check for changes in the number or appearance of different types of blood cells; a bone marrow aspiration, in which a sample of liquid bone marrow is removed to test for cancer cells; a bone marrow biopsy, in which a sample of liquid bone marrow and a small piece of bone are removed to test for cancer cells; and a routine microscopic exam to examine a sample of blood, bone marrow, lymph node tissue, or cerebrospinal fluid. Bone, blood marrow, lymph node tissue, or cerebrospinal fluid tests can distinguish among types of leukemia. A cytogenetic analysis can look for certain changes of the chromosomes (most often to test for the Philadelphia chromosome). Additional tests include a chest X ray, which may detect signs of lung infection; a computed tomography (CT) scan, a type of X ray that uses a computer to make pictures of structures inside the body; a magnetic resonance imaging (MRI) scan, which uses magnetic waves to make pictures of structures inside the body; and an ultrasound, which uses sound waves to examine masses and organs inside the body.
Treatment and Therapy
Patients should talk to their doctors about the best plans for them. The National Cancer Institute recommends patents ask their doctors about the possibility of taking part in a clinical trial. Treatment options include targeted drug therapy. Three drugs work to inhibit the molecule that triggers the development of leukemia and the gene that is associated with it. This medication is often used in the early stages of CML, and it has replaced chemotherapy and biologic therapy as a treatment of choice. The drugs for this therapy are imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna).
Chemotherapy is the use of drugs to kill cancer cells. It may be given in many forms, including by pill, injection, and catheter. The drugs enter the bloodstream and travel through the body. While these drugs will focus on cancer cells, some healthy cells will also be killed.
Biologic therapy is the use of medications or substances made by the body. The substance is used to increase or restore the body’s natural defenses against cancer. This type of therapy is also called biological response modifier therapy.
High-dose chemotherapy with stem cell transplant is another treatment option. In this treatment, high doses of chemotherapy are followed by a transplantation of stem cells (immature blood cells); these will replace blood-forming cells destroyed by cancer treatment. Stem cells are removed from the blood or bone marrow of the patient or a donor. They are then infused into the patient.
Donor lymphocyte infusion is another form of treatment. Lymphocytes are a type of white blood cell. A donor’s cells are infused into the patient. The cancer cells do not recognize these cells, and they do not attack them.
Splenectomy, a surgery to remove the spleen, may be done if the spleen has become enlarged from the leukemia. It may also be done if other complications develop.
Prevention and Outcomes
There are no guidelines for preventing CML. It is possible that smoking is associated with CML, so patients may reduce their risk by not smoking. The ten-year survival rate for individuals with the most common form of CML is 85 percent.
Bibliography
Bilal, Abdulmawjood, Beatriz Costa, Catarina Roma-Rodrigues, Pedro V. Baptista, and Alexandra R. Fernandes. "Genetic Biomarkers in Chronic Myeloid Leukemia: What Have We Learned So Far?" International Journal of Molecular Sciences, vol. 22, no. 22, 2021, DOI: 10.3390/ijms222212516. Accessed 10 Sept. 2024.
Carella, Angelo M., et al., eds. Chronic Myeloid Leukaemia: Biology and Treatment. London: Dunitz, 2001. Print.
"Chronic Myeloid Leukemia (CML)." Leukemia & Lymphoma Society, 2024, www.lls.org/research/chronic-myeloid-leukemia-cml. Accessed 10 Sept. 2024.
"Chronic Myelogenous Leukemia Treatment." National Cancer Institute, 17 Nov. 2023, www.cancer.gov/types/leukemia/patient/cml-treatment-pdq. Accessed 10 Sept. 2024.
Cortes, Jorge, and Michael Deininger, eds. Chronic Myeloid Leukemia. New York: Informa Healthcare, 2007. Print.
Fioretos, Thoas, and Bertil Johansson. “Chronic Myeloid Leukemia.” Cancer Cytogenetics. Ed. Sverre Heim and Felix Mitelman. 3d ed. Hoboken: Wiley, 2009. Print.
Lacroix, Mark. Coding for Disease: Genes and Cancer. New York: Nova Science, 2013. Print.
Mughal, Tariq I. Chronic Myeloid Leukemia: A Handbook for Oncologists and Hematologists. Boca Raton: CRC, 2013. Print.
Mughal, Tariq I., and John M. Goldman, eds. Chronic Myeloproliferative Disorders. London: Informa Healthcare, 2008. Print.
Wapner, Jessica. The Philadelphia Chromosome: A Mutant Gene and the Quest to Cure Cancer at the Genetic Level. New York: The Experiment, 2013. Print.