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

Acute and Chronic Myeloid Leukemia Part 3 Immunophenotype and Relevance to the WHO Classification The immunophenotype of human leukemia cells can be studied by multiparameter flow cyt

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 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 useful, widely used, and, in some cases, essential for the diagnosis of

AML, it is only supportive in establishing the different subtypes of AML through the 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 and subclassifies this group based on the specific types of prior chemotherapy received It also divides AML with multilineage dysplasia based upon the presence

or absence of an antecedent MDS These clinical features contribute to the prognosis of the specific type of AML

Genetic Findings and Relevance to the WHO Classification

The WHO classification is the first AML classification to incorporate genetic (chromosomal and molecular) information Indeed, AML is first subclassified based on the presence or absence of specific recurrent genetic

abnormalities For example, AML FAB M3 is now designated acute

promyelocytic leukemia (APL), based on the presence of either the

t(15;17)(q22;q12) cytogenetic rearrangement or the PML/RARα product of the

translocation Thus, the WHO classification separates APL from all other types of AML as a first step and forces the clinician to correctly identify the entity and tailor treatment(s) accordingly

Chromosomal Analyses

Chromosomal analysis of the leukemic cell provides the most important pretreatment prognostic information in AML Two cytogenetic abnormalities have been invariably associated with specific morphologic features: t(l5;17)(q22;q12) with APL and inv(16)(p13q22) with AML with abnormal bone marrow eosinophils Many other chromosomal abnormalities have been associated primarily with one morphologic/immunophenotypic group, including t(8;21)(q22;q22) with slender Auer rods, expression of CD19, and abundance of normal eosinophils, and t(9;11)(p22;q23), as well as other translocations involving 11q23, with monocytic features Many of the recurring chromosomal abnormalities in AML have been associated with specific clinical characteristics More commonly associated with younger age are t(8;21) and t(l5;17); with older age, 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 revealed genes that may be involved in leukemogenesis; this information is increasingly being incorporated into the WHO classification For instance, the t(15;17) encodes

a chimeric protein, promyelocytic leukemia (Pml)/retinoic acid receptor α (Rarα),

which is formed by the fusion of the retinoic acid receptor α (RARα) gene from

chromosome 17 and the promyelocytic leukemia (PML) gene from chromosome

15 The RARα gene encodes a member of the nuclear hormone receptor family of transcription factors After binding retinoic acid, RARα can promote expression of

a 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 Three different breakpoints in the PML gene lead to various fusion proteins The

Pml-Rar α fusion protein tends to suppress gene transcription and blocks differentiation

of the cells Pharmacologic doses of the Rar α ligand, all-trans-retinoic acid

(tretinoin), relieve the block and promote differentiation (see below) Similar examples 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 for classifying risk of relapse in patients without cytogenetic abnormalities A partial

tandem duplication (PTD) of the MLL gene is found in 5–10% of patients with

normal cytogenetics and results in short remission duration FMS-like tyrosine kinase 3 (Flt3) is a tyrosine kinase receptor important in the development of

myeloid and lymphoid lineages Activating mutations of the gene FLT3 are

present in ~30% of adult AML patients due to internal tandem duplications (ITDs)

in the juxtamembrane domain or mutations of the activating loop of the kinase These occur more commonly in patients with normal karyotype Continuous activation of Flt3 and downstream target kinases, including signal transducer and

activator of transcription protein 5, Ras/mitogen-activated protein kinase, and phosphatidylinositol 3-kinase/Akt, provides increased proliferation and

antiapoptotic signals to the myeloid progenitor cell Presence of FLT3 ITD in

patients with normal cytogenetics predicts for short remission duration and inferior survival Other molecular prognostic factors in patients with normal karyotype

AML include mutations of the nucleophosmin gene (NPM1) and C/EBP α that are

associated with improved treatment outcome In contrast, overexpression of genes

such as brain and acute leukemia, cytoplasmic (BAALC) predicts for poor

outcome Gene expression profiles to predict outcome in normal karyotype AML patients are under active investigation