Thompson & Thompson Genetics in Medicine, 8th Edition

Case 10. Chronic Myelogenous Leukemia (BCR-ABL1 Oncogene)

Somatic Mutation


• Chromosomal abnormality

• Oncogene activation

• Fusion protein

• Multihit hypothesis

• Therapy targeted to an oncogene

Major Phenotypic Features

• Age at onset: Middle to late adulthood

• Leukocytosis

• Splenomegaly

• Fatigue and malaise

History and Physical Findings

E.S., a 45-year-old woman, presented to her family physician for her annual checkup. She had been in good health and had no specific complaints. On examination, she had a palpable spleen tip but no other abnormal findings. Results of her complete blood count unexpectedly showed an elevated white blood cell count of 31 × 109/L and a platelet count of 650 × 109/L. The peripheral smear revealed basophilia and immature granulocytes. Her physician referred her to the oncology department for further evaluation. Her bone marrow was found to be hypercellular with an increased number of myeloid and megakaryocytic cells and an increased ratio of myeloid to erythroid cells. Cytogenetic analysis of her marrow identified several myeloid cells with a Philadelphia chromosome, der(22)t(9;22)(q34;q11.2). Her oncologist explained that she had chronic myelogenous leukemia, which, although indolent now, had a substantial risk for becoming a life-threatening leukemia in the next few years. She was also advised that although the only potentially curative therapy currently available is allogeneic bone marrow transplantation, newly developed drug therapy targeting the function of the oncogene in chronic myelogenous leukemia is able to induce or to maintain long-lasting remissions.


Disease Etiology and Incidence

Chronic myelogenous leukemia (CML, MIM 608232) is a clonal expansion of transformed hematopoietic progenitor cells that increases circulating myeloid cells. Transformation of progenitor cells occurs by expression of the BCR-ABL1 oncogene. CML accounts for 15% of adult leukemia and has an incidence of 1 to 2 per 100,000; the age-adjusted incidence is higher in men than in women (1.3 to 1.7 versus 1.0; see Chapter 15).


Approximately 95% of patients with CML have a Philadelphia chromosome; the remainder have complex or variant translocations (see Chapter 15). The Abelson proto-oncogene (ABL1), which encodes a nonreceptor tyrosine kinase, resides on 9q34, and the breakpoint cluster region gene (BCR), which encodes a phosphoprotein, resides on 22q11. During the formation of the Philadelphia chromosome, the ABL1gene is disrupted in intron 1 and the BCR gene in one of three breakpoint cluster regions; the BCR and ABL1 gene fragments are joined head to tail on the derivative chromosome 22 (Fig. C-10). The BCR-ABL1fusion gene on the derivative chromosome 22 generates a fusion protein that varies in size according to the length of the BCR peptide attached to the amino terminus.


FIGURE C-10 FISH analysis in metaphase and interphase (inset) cells for the detection of the t(9;22)(q34;q11.2) in CML. The DNA is counterstained with DAPI. The probe is a mixture of DNA probes specific for the BCR gene (red) at 22q11.2 and for the ABL1 gene (green) at 9q34. In cells with the t(9;22), a green signal is observed on the normal chromosome 9 (arrowhead) and a red signal on the normal chromosome 22 (short arrow). As a result of the translocation of ABL1 to the der(22) chromosome, a yellow fusion signal (long arrow) is observed from the presence of both green and red signals together on the Philadelphia chromosome. See Sources & Acknowledgments.

To date, the normal functions of ABL1 and BCR have not been clearly defined. ABL1 has been conserved fairly well throughout metazoan evolution. It is found in both the nucleus and cytoplasm and as a myristolated product associated with the inner cytoplasmic membrane. The relative abundance of ABL1 in these compartments varies among cell types and in response to stimuli. ABL1 participates in the cell cycle, stress responses, integrin signaling, and neural development. The functional domains of BCR include a coiled-coil motif for polymerization with other proteins, a serine-threonine kinase domain, a GDP-GTP exchange domain involved in regulation of Ras family members, and a guanosine triphosphatase–activating domain for regulating Rac and Rho GTPases.

Expression of ABL1 does not result in cellular transformation, whereas expression of the BCR-ABL1 fusion protein does. Transgenic mice expressing BCR-ABL1 develop acute leukemia at birth, and infection of normal mice with a retrovirus expressing BCR-ABL1 causes a variety of acute and chronic leukemias, depending on the genetic background. In contrast to ABL1, BCR-ABL1 has constitutive tyrosine kinase activity and is confined to the cytoplasm, where it avidly binds actin microfilaments. BCR-ABL1 phosphorylates several cytoplasmic substrates and thereby activates signaling cascades that control growth and differentiation and possibly adhesion of hematopoietic cells. Unregulated activation of these signaling pathways results in unregulated proliferation of the hematopoietic stem cell, release of immature cells from the marrow, and ultimately CML.

As CML progresses, it becomes increasingly aggressive. During this evolution, tumor cells of 50% to 80% of patients acquire additional chromosomal changes (trisomy 8, i(17q), or trisomy 19), another Philadelphia chromosome, or both. In addition to the cytogenetic changes, tumor-suppressor genes and proto-oncogenes are also frequently mutated in the progression of CML.

Phenotype and Natural History

CML is a biphasic or triphasic disease. The initial or chronic stage is characterized by an insidious onset with subsequent development of fatigue, malaise, weight loss, and minimal to moderate splenic enlargement. Over time, CML typically evolves to an accelerated phase and then to a blast crisis, although some patients progress directly from the chronic phase to the blast crisis. CML progression includes development of additional chromosomal abnormalities within tumor cells, progressive leukocytosis, anemia, thrombocytosis or thrombocytopenia, increasing splenomegaly, fever, and bone lesions. Blast crisis is an acute leukemia in which the blasts can be myeloid, lymphoid, erythroid, or undifferentiated. The accelerated phase is intermediate between the chronic phase and blast crisis.

Approximately 85% of patients are diagnosed in the chronic phase. Depending on the study, the median age at diagnosis ranges from 45 to 65 years, although all ages can be affected. Untreated, the rate of progression from the chronic phase to blast crisis is approximately 5% to 10% during the first 2 years and then 20% per year subsequently. Because blast crisis is rapidly fatal, demise parallels progression to blast crisis.


Recognition of the molecular basis of CML led to the development of a specific BCR-ABL1 tyrosine kinase inhibitor, imatinib mesylate (Gleevec). This drug is now the first line of treatment for CML. More than 85% of patients have a clear cytogenetic response after imatinib therapy, with disappearance of the t(9;22) in cells obtained by bone marrow aspirates. Cytogenetic response corresponds to a large reduction in CML disease burden to levels below 109 to 1010 leukemic cells. Few patients (<5%), however, show no evidence of the BCR-ABL1 fusion gene by polymerase chain reaction analysis, indicating that even in remission, most patients have a residual leukemia burden of at least 106 to 107 cells. Of patients with complete hematological and cytogenetic remission, more than 95% remained in control for more than 3.5 years. Patients in blast crisis also respond with improved 12-month survival of 32%, but relapses are common. In these patients, imatinib resistance is frequent (60% to 90%), in association with point mutations that render the ABL1 kinase resistant to the drug or, less commonly, with BCR-ABL1 gene amplification.

Although allogeneic bone marrow transplantation (BMT) is the only known curative therapy, the success of imatinib mesylate has limited the population of patients to whom BMT is offered to those with the highest success rate (patients younger than 40 years with an HLA-matched sibling donor, in whom BMT success is quoted at 80%) and to those in blast crisis. The success of BMT depends on the stage of CML, the age and health of the patient, the bone marrow donor (related versus unrelated), the preparative regimen, the development of graft-versus-host disease, and the post-transplantation treatment. Much of the long-term success of BMT depends on a graft-versus-leukemia effect, that is, a graft-versus-host response directed against the leukemic cells. After BMT, patients are monitored frequently for relapse by reverse transcriptase polymerase chain reaction to detect BCR-ABL1 transcripts and treated as necessary. If BMT fails, patients often respond to infusion of BMT donor-derived T cells, consistent with a graft-versus-leukemia mechanism of action of BMT for CML.

Patients in blast crisis are usually treated with imatinib mesylate, cytotoxic agents and, if possible, BMT. Unfortunately, only 30% of patients have a related or unrelated HLA-matched bone marrow donor. The outcome of these therapies for blast crisis remains poor.

Inheritance Risk

Because CML arises from a somatic mutation that is not found in the germline, the risk for a patient's passing the disease to his or her children is zero.

Questions for Small Group Discussion

1. What is the multihit hypothesis? How does it apply to neoplasia?

2. Discuss two additional mechanisms of proto-oncogene activation in human cancer.

3. Neoplasias graphically illustrate the effects of the accumulation of somatic mutations; however, other less dramatic diseases arise, at least in part, through the accumulation of somatic mutations. Discuss the effect of somatic mutations on aging.

4. Many somatic mutations and cytogenetic rearrangements are never detected because the cells containing them do not have a selective advantage. What advantage does the Philadelphia chromosome confer?

5. Name other cancers caused by fusion genes resulting in oncogene activation. Which others have been successfully targeted?


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Jabbour E, Cortes J, Ravandi F, et al. Targeted therapies in hematology and their impact on patient care: chronic and acute myeloid leukemia. Semin Hematol. 2013;50:271–283.

Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353:172–187.