Chapter 104. Acute and Chronic Myeloid Leukemia (Part 3)

Immunophenotype and Relevance to the WHO ClassificationThe immunophenotype of human leukemia cells can be studied by multiparameter flow cytometry after the cells are labeled with monoclonal antibodies to cell-surface antigens. This can be important for separating AML from acute lymphoblastic leukemia (ALL) and identifying some types of AML. For example, AML that is minimally differentiated (immature morphology and no lineage-specific cytochemical reactions) is diagnosed by flow-cytometric demonstration of the myeloid-specific antigens cluster designation (CD) 13 or 33. Similarly, acute megakaryoblastic leukemia can often be diagnosed only by expression of the platelet-specific antigens CD41 and/or CD61. While flow cytometry is...
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Chapter 104. Acute and Chronic Myeloid Leukemia (Part 3) Chapter 104. Acute and Chronic Myeloid Leukemia (Part 3) Immunophenotype and Relevance to the WHO Classification The immunophenotype of human leukemia cells can be studied bymultiparameter flow cytometry after the cells are labeled with monoclonalantibodies to cell-surface antigens. This can be important for separating AMLfrom acute lymphoblastic leukemia (ALL) and identifying some types of AML.For example, AML that is minimally differentiated (immature morphology and nolineage-specific cytochemical reactions) is diagnosed by flow-cytometricdemonstration of the myeloid-specific antigens cluster designation (CD) 13 or 33.Similarly, acute megakaryoblastic leukemia can often be diagnosed only byexpression of the platelet-specific antigens CD41 and/or CD61. While flowcytometry is useful, widely used, and, in some cases, essential for the diagnosis ofAML, it is only supportive in establishing the different subtypes of AML throughthe WHO classification. Clinical Features and Relevance to the WHO Classification The WHO classification considers clinical features in subdividing AML.For example, it identifies therapy-related AML as a separate entity andsubclassifies this group based on the specific types of prior chemotherapyreceived. It also divides AML with multilineage dysplasia based upon the presenceor absence of an antecedent MDS. These clinical features contribute to theprognosis of the specific type of AML. Genetic Findings and Relevance to the WHO Classification The WHO classification is the first AML classification to incorporategenetic (chromosomal and molecular) information. Indeed, AML is firstsubclassified based on the presence or absence of specific recurrent geneticabnormalities. For example, AML FAB M3 is now designated acutepromyelocytic leukemia (APL), based on the presence of either thet(15;17)(q22;q12) cytogenetic rearrangement or the PML/RARα product of thetranslocation. Thus, the WHO classification separates APL from all other types ofAML as a first step and forces the clinician to correctly identify the entity andtailor treatment(s) accordingly. Chromosomal Analyses Chromosomal analysis of the leukemic cell provides the most importantpretreatment prognostic information in AML. Two cytogenetic abnormalities havebeen invariably associated with specific morphologic features: t(l5;17)(q22;q12)with APL and inv(16)(p13q22) with AML with abnormal bone marroweosinophils. Many other chromosomal abnormalities have been associatedprimarily with one morphologic/immunophenotypic group, includingt(8;21)(q22;q22) with slender Auer rods, expression of CD19, and abundance ofnormal eosinophils, and t(9;11)(p22;q23), as well as other translocations involving11q23, with monocytic features. Many of the recurring chromosomalabnormalities in AML have been associated with specific clinical characteristics.More commonly associated with younger age are t(8;21) and t(l5;17); with olderage, del(5q) and del(7q). Myeloid sarcomas (see below) are associated with t(8;21)and disseminated intravascular coagulation (DIC) with t(15;17). Molecular Classification Molecular study of many recurring cytogenetic abnormalities has revealedgenes that may be involved in leukemogenesis; this information is increasinglybeing incorporated into the WHO classification. For instance, the t(15;17) encodesa chimeric protein, promyelocytic leukemia (Pml)/retinoic acid receptor α (Rarα),which is formed by the fusion of the retinoic acid receptor α (RARα) gene fromchromosome 17 and the promyelocytic leukemia (PML) gene from chromosome15. The RARα gene encodes a member of the nuclear hormone receptor family oftranscription factors. After binding retinoic acid, RARα can promote expression ofa variety of genes. The 15;17 translocation juxtaposes PML with RARα in a head-to-tail configuration that is under the transcriptional control of PML. Threedifferent breakpoints in the PML gene lead to various fusion proteins. The Pml-Rar α fusion protein tends to suppress gene transcription and blocks differentiationof the cells. Pharmacologic doses of the Rar α ligand, all-trans-retinoic acid(tretinoin), relieve the block and promote differentiation (see below). Similarexamples exist with a variety of other balanced translocations and inversions,including the t(8;21), t(9;11), t(6;9), and inv(16). Molecular aberrations are also being identified that are useful forclassifying risk of relapse in patients without cytogenetic abnormalities. A partialtandem duplication (PTD) of the MLL gene is found in 5–10% of patients withnormal cytogenetics and results in short remission d ...