Question

Name and describe four functional properties of the Bcr-Abl fusion protein that contribute to disease progression in CML. Also describe whether these would be gain of function or loss of function mutations with respect to normal Abl kinase activity. Please bullet point your response for ease of grading.

Answer 1

The four functional properties of Bcr-Abl fusion protein are :

1) Clonogenicity- Bcr-Abl gene produces protein tyrosine kinase that allows to clone white blood cells multiple times. So these cells will contain abnormal Philadelphia chromosome that progresses the CML disease.

2) Disturbance of normal granulocyte differentiation- The white blood cells with abnormal Philadelphia chromosome multiplies and accumulates in the bone marrow and disturbs the normal granulocyte differentiation.

3) Prevention of apoptosis- Bcl-Abl gene produces tyrosine kinase that clones abnormal Philadelphia chromosomes. These chromosomes keeps on expressing more Bcl-Abl genes. So with higher levels of their expression in our body leads to deactivation of apoptosis.

4) Distribution of white blood cells with abnormal Philadelphia chromosome- Bcl-Abl gene mainly affects the bone marrow from where red blood cells and white blood cells are formed. So the white blood cells with the abnormal chromosome keeps on cloning and then spreads through the blood.

Normal Abl kinase has the ability for cell proliferation, cell differentiation, cell death, cell migration and withdrawal of unwanted cell proliferation or differentiation. In CML disease, we can observe that Bcl-Abl gene produces tyrosine kinase that proliferates cells in an unregulated way and deactivated apoptosis process too. It kept on functioning like this and distributed the cancerous cells throughout the body. So this shows loss of functions of Abl kinase activity in case of cell death function and withdrawal of unwanted cell proliferation and differentiation.