CML (Chronic myeloid leukemia) - Genes BCR, ABL1, chromosome 9 and chromosome 22

Chronic myeloid leukemia (CML), also known as myelogenous leukemia, is a chronic myeloproliferative syndrome characterized by an uncontrolled proliferation of white blood cells of the granulocytic series. Over time, these cells invade the bone marrow and the rest of the body, preventing the normal production of other blood cells and altering operation of various organs.

Clinical manifestations of individuals with chronic myeloid leukemia usually begins after age 60, and may include extreme fatigue, fever and weight loss. Many affected individuals develop splenomegaly, which may cause bloating in the abdomen and loss of appetite. About half of people with chronic myelogenous leukemia initially show no signs or symptoms and is usually diagnosed when a blood test is done for another reason.

Chronic myeloid leukemia consists of three phases: the chronic phase, accelerated phase, and blastic phase (or blast crisis). In the chronic phase, the number of mature leukocytes is elevated, and myeloblasts represent less than 10 percent of blood cells. Signs and symptoms of the disease during this phase are generally mild or absent and progress slowly; chronic phase can last from months to years. In the accelerated phase, the number of myeloblasts is slightly higher, and constitute from 10 to 29 percent of blood cells. Signs and symptoms continue to worsen. Accelerated usually lasts 4 to 6 months phase, although omitted in some affected individuals. In blast crisis, myeloblasts represent 30 percent or more of the blood cells or bone marrow. Signs and symptoms are more severe at this stage, and include an enlarged spleen massively, bone pain and weight loss. Severe infections and bleeding can not be controlled potentially fatal.

Chronic myeloid leukemia is due to a translocation of genetic material between chromosomes 9 and 22. This translocation, t (9; 22), produces a reordering fusing part of the BCR gene (BCR, RhoGEF and GTPase activating protein), located in the long arm of chromosome 22 (22q11.23) and part of ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) gene, located on the long arm of chromosome 9 (9q34.1). This chromosome abnormality resulting in the formation of the Ph chromosome ( "Philadelphia") and the formation of two hybrid genes. The first BCR-ABL1 is located on the long arm of chromosome 22 or chromosome Ph; the second, called BCR-ABL1 and located on chromosome 9q + derivative, is reciprocal to the first and does not seem to play any role in the disease. The resulting protein BCR-ABL1 gene is a tyrosine kinase constitutively active it promotes survival and continued cell proliferation and inhibits apoptosis. This leads to an overproduction of abnormal cells and, eventually, a deficiency of normal blood cells.

In 5 to 10 percent of cases of chronic myeloid leukemia, the fusion gene BCR-ABL1 is created by complex rearrangements involving other chromosomes, apart from chromosomes 9 and 22. These genetic changes are called variants translocations Ph ( "Philadelphia"). These cases are similar to those caused by t (9; 22).

It is believed that certain additional genetic changes play a role in the progression of the chronic phase of the disease to accelerated phase and blastic phase. The most common genetic changes associated with progression to blast crisis include an extra copy of chromosome 8 (trisomy 8), an abnormality of chromosome 17 and duplication of chromosome Ph ( "Philadelphia"). When these mutations occur in somatic cells with the Philadelphia chromosome, it is likely to further promote uncontrolled cell proliferation.

Chronic myeloid leukemia usually not inherited, but arises from a mutation in the body cells that occurs after conception. This alteration is called a somatic mutation.

Tests in IVAMI: in IVAMI perform detection of mutations associated with chronic myeloid leukemia, by complete PCR amplification of the exons of the BCR and ABL1 genes, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).