Chronic myelogenous leukemia and the Philadelphia chromosome

Chronic myelogenous leukemia (CML) is the archetypal example of a group of bone marrow disorders collectively known as myeloproliferative neoplasms (MPNs). These conditions are characterized by a clonal proliferation of mature cell products of myeloid lineage. Though all MPNs demonstrate an increase in all of the mature myeloid products, they are classified on the basis of which cell type is predominant. In the setting of CML, the dominant cell is the granulocyte (myelocyte), most notably, the basophil. Figure $1$‍ shows the basic schematic of hematopoiesis.

Figure 1: Hematopoiesis and mature cell products.

Like all neoplastic disorders, CML is characterized by the loss of important regulatory factors controlling cell growth, differentiation, proliferation, and/or cell death. The mechanism by which this dysregulation occurs in CML is due to the development of a unique chromosomal abnormality, commonly referred to as the “Philadelphia chromosome”. The presence of this genetic aberration is important in differentiating CML from other pathologic disorders such as the leukemoid reaction. ‘Leukemoid reaction’ simply refers to the normal body response to many infections, leading to a proliferation of leukocytes (leukocytosis), which may resemble CML under the microscope.

The Philadelphia chromosome arises from a translocation between chromosomes $9$‍ and $22$‍, producing an elongated $c9$‍, and a truncated $c22$‍ (shown in Figure $2$‍). The result of the $t(9;22)$‍ change is the fusion of the BCR (breakpoint cluster region) gene on $c22$‍ with the ABL1 gene of $c9$‍. In its normal position, the ABL1 gene codes for a membrane associated tyrosine kinase, which serves as the ‘on-off’ switch for numerous cellular functions.

The Philadelphia translocation product, the BCR-ABL1 protein, translates into a continuously activated version of the same tyrosine kinase (ABL1), leading to unregulated growth and division of the mutated cell and all resulting daughter cells. Common symptoms of CML result from the overabundance of myeloid lineage cells and include fatigue, weight loss, night sweats, fever, and an enlarged spleen (splenomegaly).