Acute Myeloid Leukemia and CDC20 gene
Acute myeloid leukaemia (AML) is fast progressing cancer of the blood which originates in the bone marrow. The maturities of the bone marrow cells are prevented in AML. Instead, immature blast cells with increased capacity of mitosis are released into the blood. Around 11 billion blast cells are formed and released from the bone marrow. Thus, AML is a process whereby the hematopoietic precursor cells are transformed in such a way leading to limitless cell cycles and cell divisions. These cells do not undergo apoptosis or programmed cell death, which leads to the progression of cancer. AML is also designated by other classifications like myelocytic, granulocytic, myelogenous and non-lymphocytic leukaemia. In this type of leukaemia the affected cells are RBCs, WBCs and Platelets but do not include lymphocytes. AML can affect various organs like the lymph nodes, liver, spleen and testicles (1).
The risk factors for AML includes smoking, chronic exposure to benzene (as it damages the DNA of bone marrow cells), chemotherapeutic treatment with alkylating agents and topoisomerase II inhibitors and presence of Down’s syndrome or Fanconi anaemia. AML may also be potentiated by polycythemia or myelofibrosis or other forms of blood cancer. AML is the most common form of acute leukaemia which affects older people. It is more prevalent in individuals >60 years of age and predominantly occurs in males. However, 15% to 25% cases of childhood acute leukaemia are due to AML. The risk of AML increases to around 10 fold from the age range of 30-34 years to the age range in 65 to 69 years. During the former age range there is a prevalence of AML in 1 out of 100,000 while in the later age range the prevalence of AML is 10 out of 100,000. Beyond the age of 70 years till the age of 85 years the prevalence is far higher.
Cdc20 is a specific cell division checkpoint protein which helps in the activation of the anaphase-promoting complex (APC). It is the product of the cdc20 gene. For, a cell to undergo mitosis (cell division), anaphase is an important step. In this step the sister chromatids are separated and start to move towards different poles from the equatorial plate (metaphase). This arrangement is important for cell division. Hence, cdc20 helps in normal cell division and progression of cancer cells (metastasis). Cdc20 binds to phosphorylated APC and activates it. Increased activation of APC/cyclin complex leads to inhibition of a protein called, Securin. Securin inhibits a cell from entering the Anaphase because it prevents the separation of chromatids to the opposite poles. Activation of APC thus helps a cell to enter the anaphase by overcoming the inhibition of Securin. Cdc20 also inhibits the cyclin-dependent kinase which was used to phosphorylate APC, after the mitotic phase is over. Hence, cdc20 acts as cell cycle checkpoints and regulates both mitosis and also inhibits premature mitosis (2).
Spindle assembly checkpoint (SAC) acts as a monitor to detect the proper alignment of chromosomes to the mitotic spindles before anaphase or cell division ensues. Thus, SAC acts as an inhibitor of APC-cdc20, and controls accurate mitosis. However, when chromosomal misalignment occurs, mitotic checkpoint complex (MCC) consisting of three proteins Mad2, Bub3 and BubR1 attach to APC-cdc20 and inactivate it. Thus premature mitosis is prevented. In cases of malignancy this mechanism of inhibition is weakened which causes the cancerous cells to gain or lose genetic material. In AML, there is an abnormal expression of a protein called AML-1ETO which causes the chromosomal aberrations (3).
Truncated AML-1ETO has been demonstrated to interfere with the integrity of SAC. Hence, these cells produced repressed amounts of BubR1. Decreased BubR1 resulted in ineffective inhibition of APC-cdc20, which causes premature mitosis and progression of cancer in AML(3).Kasumi-1 cells (low BubR1 expressed, myeloblastic cells) and HL-60 cell line (AML cells showing normal BubR1 expression) were transfected with retrovirus-delivered BubR1. When induced by doxycycline the expression of Bub1 expression was increased these cells (4). Thus it may be predicted that BUbR1 expressions will lead to inhibition of APc-cdc20 and inhibit premature mitosis. Targeting cdc-20 holds a promise for alleviating AML as inhibition of cdc20 and thus APC will prevent premature mitosis and progression of immature blasts into the blood.
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Schnerch,D;* Schmidts,A; Follo,M; Udi, J; Felthaus, J; Pfeifer,D; Engelhardt, M; & Wäsch;R. BubR1 is frequently repressed in acute myeloid leukemia and its re-expression sensitizes cells to antimitotic therapy Haematologica. 2013 Dec; 98(12): 1886–1895
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