-LMC- chronic myeloid leukemia. Imatinib (Chronic myeloid leukemia -CML-) - WT1 genes, BCR ABL, chromosome 9, chromosome 17 and chromosome 22.

Chronic myeloid leukemia (CML), also known as chronic granulocytic leukemia or myelogenous leukemia, is a chronic myeloproliferative syndrome characterized by uncontrolled proliferation of granulocytic leukocytes. 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. CML represents about 10% of total cases of leukemia.

In most cases, CML is due to chromosomal translocation type t (9; 22) (q34; q11), which produces a rearrangement of the BCR gene, located on the long arm of chromosome 22 (22q11.23 ) and ABL, 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 is BCR-ABL, located on the long arm of chromosome 22 or chromosome Ph; the second, called BCR-ABL and located on chromosome 9q + derivative, is reciprocal to the first and does not seem to play any role in the disease. The resulting BCR-ABL protein gene is a constitutively active tyrosine kinase that promotes survival and continued cell proliferation and inhibits apoptosis.

In a smaller number of people with chronic myelogenous leukemia it has identified an abnormality on chromosome 17q 17 isochromosome called. This abnormal version of chromosome 17 has two long arms instead of a long arm and a short arm. As a result, chromosome 17 has an additional copy of some genes and lost or absent from other genes copies.

In a few cases they have been identified changes in the WT1 gene, located on the short arm of chromosome 11 (11p13), related to various cancers including chronic myeloid leukemia. The WT1 gene encodes a protein transcription factor that is required for the development of kidney and gonads. Within these tissues, the WT1 protein plays a role in cell growth, cell differentiation and apoptosis. However, it is unclear what role the WT1 protein in the development or progression of this type of leukemia.

Imatinib (Gleevec®) is a small molecule that acts as a selective inhibitor of tyrosine kinase BCR - ABL joining each of the ATP binding sites when the activation loop of the kinase is closed. Stabilizes the protein upon binding, keeping the inactive conformation. Thus, it causes a remission in chronic myeloid leukemia (CML) by a deletion of chromosome bearing cells Ph. Given its high initial effectiveness has become the standard treatment to treat CML.

However, cases have been detected increasing clinical resistance to imatinib. The most common mechanisms for development of resistance to imatinib are point mutations in the kinase domain of the protein that affect binding of imatinib by interfering directly or union or stabilize the BCR conformation - ABL (where the activation loop kinase is open) reducing the affinity of imatinib. They have been found so far a total of 17 different amino acid mutations within the kinase domain associated with clinical resistance to imatinib in patients with chronic myeloid leukemia.

Genetic changes that lead to the development of chronic myeloid leukemia, arising from somatic mutations occurring in the body cells after conception, which means that are acquired during the lifetime of a person and are present only in certain types cell.

Tests in IVAMI: IVAMI performed in detecting mutations associated with the development of chronic myeloid leukemia (CML), by complete PCR amplification of the exons of the WT1 gene, and subsequent sequencing. We also perform the genetic study of chromosomes 9, 17 and 22 to determine whether there are chromosomal abnormalities involved in the development of the condition. On the other hand, we perform sequencing BCR-ABL gene resulting from chromosomal translocation of type t (9; 22) (q34; q11), in screening for mutations associated with the development of resistance to imatinib, by amplification via PCR 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).