Chronic Myelogenous Leukemia Pathogenesis

Cancer pathology and leukemia

Normally there is DNA or cellular blue prints that govern a cell’s life including its growth, maturity, multiplication and eventual death. When the DNA is mutated, cells often grow and divide uncontrollably. This leads to formation of tumors and eventually cancer.

The cells grow with the nutrients essential for the organism and also grow to press upon the space of other organs. Tumors may be benign when they multiply but rarely spread to other organs or may me more aggressive when they spread to other organs.

Leukemia is the cancer of the cells within the bone marrow and those in blood. Here the stem cells of the bone marrow that produce cells of the blood including red blood cells, white blood cells or platelets, multiply uncontrollably. Specific series of these cells multiply and this leads to a deficiency of other cellular lines.

Types of leukemia

Leukemias may be acute or chronic depending on their progression. Acute leukemias progress rapidly and chronic leukemias progress slowly.

If the cancerous change takes place in a type of marrow cell that forms lymphocytes, the leukemia is called lymphocytic, lymphoid (or lymphoblastic) and if the change takes place in a type of marrow cell that normally goes on to form red blood cells, some kinds of white blood cells and platelets, the leukemia is called myeloid type. Thus there are four major types of leukemia:-

• Acute lymphoblastic Leukemia (ALL)
• Acute myeloid leukemia (AML)
• Chronic lymphoblastic leukemia (CLL)
• Chronic myeloid leukemia (CML)

The four main types of leukemia are further classified into subtypes based on features of cells. Knowing the subtype of leukemia helps plan the treatment and assesses the possible outcome of the disease.

Pathogenesis of CML

CML is caused by change or a mutation in the DNA of a single cell in the bone marrow. This mutation is acquired after birth and is not hereditary or inherited from parents.

Normally cells with a mutated DNA are killed off by the mechanism within the cell. Sometimes this programmed death of the damaged cell fails to occur and this results in crowding out of the normal cells.

There is an uncontrolled growth of CML cells in the marrow. The precursor cells of the red blood cells and platelets are usually not affected but those of white blood cells may be affected.

Philadelphia chromosome

Normal cells have 23 pairs of chromosomes. These are thread-like structures in the nucleus of the cells that contain the DNA and genes.

There are 22 numbered pairs called autosomes and a pair of sex chromosomes (XX for a female and XY for a male) that makes up the 23rd pair.

CML was initially differentiated from other types of leukemia by the presence of a genetic abnormality of chromosome 22 in CML cells.

In 1960 researchers at the University of Pennsylvania School of Medicine in Philadelphia found that chromosome 22 in cells from patients with CML was shorter than the same chromosome in normal cells.

The shortened chromosome 22 was named the “Philadelphia chromosome” and is also called the “Ph chromosome.”

Thereafter it was found that the two chromosomes, number 9 and number 22 were abnormal because parts of these chromosomes actually switch places with each other.

A portion of chromosome 9 moves to the end of chromosome 22 and a portion of chromosome 22 moves to the end of chromosome 9. This process is called translocation. The translocation of chromosome 9 and chromosome 22 is found only in CML cells.

This gene is called BCR-ABL cancer causing gene. The broken part of the chromosome 9 leads to a mutation of a gene called “ABL”. ABL stands for Abelson, who first described this gene.

The break on chromosome 22 involves a gene called “BCR” that stands for breakpoint cluster region. The ABL gene moves to chromosome 22 and fuses with the remaining portion of the BCR gene. This results in a leukemia-causing fusion gene BCR-ABL gene.

This abnormal BCR-ABL gene produces an abnormal protein called “Bcr-Abl tyrosine kinase.” This BCR-ABL TK leads to the abnormal growth and survival of the cancer cells.

This protein BCR-ABL TK is the target of several therapies with tyrosine kinase inhibitors like Imatinib, Dasatinib and Nilotinib.

Further Reading

• All Chronic Myelogenous Leukemia Content
• What is Chronic Myelogenous Leukemia (CML)?
• Chronic Myelogenous Leukemia Symptoms
• Chronic Myelogenous Leukemia Diagnosis
• Chronic Myelogenous Leukemia Treatment

Written by

Dr. Ananya Mandal

Dr. Ananya Mandal is a doctor by profession, lecturer by vocation and a medical writer by passion. She specialized in Clinical Pharmacology after her bachelor's (MBBS). For her, health communication is not just writing complicated reviews for professionals but making medical knowledge understandable and available to the general public as well.