Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by the BCR-ABL1 fusion gene, the molecular consequence of the Philadelphia chromosome. It is the prototype of a cancer defined by a single recurrent genetic lesion, and it characteristically follows a course from an indolent chronic phase toward more aggressive accelerated and blast phases if the clone is not controlled.

Definition

Chronic myeloid leukemia is a clonal myeloproliferative neoplasm of the hematopoietic stem cell defined by the BCR-ABL1 fusion gene arising from the Philadelphia chromosome, which encodes a constitutively active tyrosine kinase that drives expansion of the granulocytic lineage.

Scope

This topic covers the biology and natural history of CML: the Philadelphia chromosome and the BCR-ABL1 fusion, the constitutively active tyrosine kinase it encodes, the three-phase clinical course, and the role of molecular monitoring. It is reference material on the disease and its scientific basis, not a treatment protocol; specific drug regimens and dosing are out of scope.

Key concepts

• Philadelphia chromosome (t(9;22))
• BCR-ABL1 fusion gene
• Constitutively active tyrosine kinase
• Chronic, accelerated, and blast phases
• BCR-ABL1 transcript monitoring
• Tyrosine kinase inhibition as targeted therapy concept
• Cytogenetic and molecular response

Mechanisms

A reciprocal translocation between chromosomes 9 and 22 creates the Philadelphia chromosome and fuses the BCR and ABL1 genes. The resulting BCR-ABL1 protein is a constitutively active tyrosine kinase that drives proliferation and survival of myeloid progenitors independent of normal growth signals, producing the expanded granulocytic mass that characterizes the disease. This single, well-defined molecular driver makes CML the paradigm of targeted cancer therapy through tyrosine kinase inhibition, and the level of BCR-ABL1 transcript provides a quantitative marker of disease burden (Rowley, 1973; Hochhaus et al., 2020).

Clinical relevance

CML is a defining example of how identifying a specific molecular driver reshapes the understanding and monitoring of a cancer, and its management is now guided by quantitative molecular response. This entry describes the disease and its biology at a reference level and does not provide individualized diagnostic or treatment recommendations.

Epidemiology

CML is an uncommon leukemia of adults, with incidence rising with age and a slight male predominance; with effective control of the driving clone, prevalence has increased as affected individuals live longer (Hochhaus et al., 2020).

Evidence & guidelines

Diagnosis, phase definition, and response milestones for CML are addressed by the WHO myeloid classification and by expert recommendations such as those of the European LeukemiaNet, which define molecular and cytogenetic response criteria and monitoring intervals (Arber et al., 2016; Hochhaus et al., 2020).

History

Nowell and Hungerford described the small marker chromosome — later named the Philadelphia chromosome — in chronic granulocytic leukemia in 1960, and Rowley showed in 1973 that it results from a reciprocal translocation between chromosomes 9 and 22. Identification of the BCR-ABL1 fusion and its kinase activity subsequently established CML as the model for molecularly targeted therapy (Nowell & Hungerford, 1960; Rowley, 1973).

Key figures

• Janet Rowley
• Peter Nowell
• David Hungerford

Seminal works

• nowell-hungerford-1960
• rowley-1973

Frequently asked questions

What causes chronic myeloid leukemia at the molecular level?

The BCR-ABL1 fusion gene, formed by the translocation that creates the Philadelphia chromosome, encodes a constitutively active tyrosine kinase that drives uncontrolled expansion of the myeloid lineage.

What are the phases of CML?

CML is classically described in three phases: a chronic phase, an accelerated phase, and a blast phase, with progression reflecting accumulating biological aggressiveness if the clone is not controlled.