Chronic Myelocytic Leukemia - Part I: History, Clinical Presentation, and Molecular Biology

Clinical Laboratory Science, Winter 2005 by Randolph, Tim R

The accelerated phase of CML is marked by an increasing WBC and basophil count, a decreasing platelet and RBC count and, most notably, an increase in circulating blasts. Increasing blasts in the presence of immature myeloid cells indicate the transformation from chronic leukemia to acute leukemia. The bone marrow shows an increased number of blasts with suppression of erythroid and megakaryocytic proliferation, which is responsible for the presence of peripheral blasts, anemia, and thrombocytopenia in the blood. The promyelocytes, myelocytes, and metamyelocytes observed in the chronic phase are more likely to be released into circulation as compared to the blasts that accumulate in the accelerated phase.

Blasts possess the necessary homing receptors to a greater degree than do their more mature counterparts, which facilitate retention in the bone marrow resulting in cellular accumulation. The increasing number of blasts and the proliferation of fibrotic tissue contribute to bone marrow suppression that produces the anemia and thrombocytopenia characteristic of the accelerated phase of CML. Symptoms of fever, night sweats, weight loss, and splenomegaly are exacerbated in the accelerated phase. Additional chromosomal mutations are observed in this stage of CML and are largely responsible for the transformation from the chronic to the acute clinical picture. The accelerated phase of CML lasts approximately six to eighteen months with 30% of patients dying prior to entering blast crisis.10

Prior to tyrosine kinase inhibitors, once a patient enters blast crisis, interventions were futile and death imminent. Both the symptoms and the peripheral blood abnormalities intensify. However, in about one fourth of CML patients, the blast crisis phase occurs without the typical transition through the accelerated phase.10 The differential reflects the increasing number of blasts and the worsening anemia and thrombocytopenia. Patients develop bleeding symptoms from the thrombocytopenia, bone tenderness from the expanding bone marrow and gouty arthritis from uric acid build-up, as cell turnover increases. The bone marrow reflects the increasing blasts, and the stage is marked by a bone marrow blast count of >30% by FAB criteria. About 25% to 35% of patients that enter blast crisis produce ALL, while about 65% to 75% result in AML. Less than 10% of cases result in acute leukemias of other lineages. Historically, death would occur in less than eight months after entering blast crisis, generally from bleeding, infection, or bone marrow aplasia. Patients with ALL blast crisis have a higher complete remission rate (60%) as compared to patients with AML blast crisis (20-30%), but the duration of remission is less than one year.11 The hopelessness associated with blast crisis is changing with the advent of targeted molecular therapy involving tyrosine kinase inhibitors.

An atypical form of CML has been observed in children. This atypical form is termed juvenile CML by the FAB group and is omitted in the WHO classification system. It accounts for between 1 % and 5% of childhood leukemias and generally affects children under five years of age. The WBC count is usually between 15 × 10^sup 9^/L and 100 × 10^sup 9^/L at diagnosis with a mean of 30 × 10^sup 9^/L. There is a slow increase in blasts and the children develop skin rashes and infections. Juvenile CML progresses faster than adult CML producing death in about two years.

MOLECULAR BIOLOGY OF t(9;22) IN CML

Our understanding of the molecular biology of the t(9;22) translocation has contributed to the current theories of leukemogenesis in CML. Once the ABL oncogene was mapped to the long arm of chromosome 9 it was quickly confirmed that the t(9;22) translocation brought together the ABL oncogene to an unknown area of chromosome 22. It was later discovered that the breakpoints that occurred on chromosome 22 clustered within a limited region on the long arm that was subsequently termed breakpoint cluster region (BCR).12Therefore, the t(9;22) translocation creates a BCR/ABL fusion gene that is transcribed into a chimeric BCR/ABL mRNA and translated into a hybrid protein.8 As can be seen in figure 1, the 9;22 translocation interrupts the ABL oncogene on chromosome 9 and the BCR gene on chromosome 22. The ABL gene is a marine viral oncogene that is 230 kilobases in length and contains 11 exons with two splice sites (Figure 2a). The ABL gene normally codes for a 145 kilodalton nuclear protein, called p 145, that possesses tyrosine kinase activity. In contrast, the BCR gene complex is composed of at least four separate genes termed BCRl, BCR2, BCR3, and BCR4. BCRl is the most common BCR gene involved in the 9;22 translocation and is illustrated in the upper panel of Figure 2a. BCRl is approximately 100 kilobases in length and divided into 20 exons with two splice sites. The gene normally codes for a 160 kilodalton protein (pi60) that is constitutively expressed in many cell types, but strongly expressed in hematopoietic cells.