Elisabeth Paietta

Acute leukemias are commonly defined as the expansion of immature cells that are derived from a single transformed hematopoietic progenitor cell. Rather than undergoing normal differentiation and/or normal programmed cell death (apopto-sis), leukemic cells engage in abnormal, uncontrolled, and therefore, indefinite proliferation. If leukemic cells had arrested somewhere along the normal hematopoietic pathway, the immunophenotypes of the acute leukemias would mirror variable stages of normal differentiation. In fact, the immunophe-notypes of most acute leukemia blasts resemble to a large degree phenotypes found among normal myeloid or lymphoid progenitor cells. However, in most cases immunophenotypic features can be recognized that distinguish the leukemic cells from normal hematopoietic cells. For instance, the European BIO-MED-1 Concerted Action, initiated to improve and standardize the flow cytometric detection of minimal residual disease in acute leukemia, demonstrated that virtually all immunopheno-types of T-lineage acute lymphoblastic leukemia (ALL) fell outside of defined normal T-ceH subsets in bone marrow, into areas of flow cytometric plots where no normal cells are found.1

Genotypic alterations associated with or responsible for the development of acute leukemia may affect the overall pheno-type of the transformed cells. This may explain the occurrence of unique antigens or antigen patterns in leukemia subtypes characterized by particular cytogenetic abnormalities.2 Examples are the frequent finding of the T-cell antigen CD2 on leukemic myeloblasts containing an inverted chromosome 16 or the combined expression of the B-lymphoid antigen CD19 and the natural killer (NK) cell antigen CD56 on leukemic myeloblasts containing an (8;21) translocation.

It is correct to state that antigens expressed by leukemic cells are the same as those that are expressed by normal hematopoi-etic cells. To date, there is no knowledge of leukemia-specific antigens, with the exception of proteins that are encoded by novel fusion genes as a result of leukemia-specific chromosomal aberrations,3 to which, however, diagnostic antibodies are not readily available. In acute promyelocytic leukemia (APL), antibodies to the PML protein, which is the product of one of the two genes involved in the PML/RARa fusion, are useful diagnostic tools owing to the unique abnormal distribution of anti-PML labeling in cells that bear the t(15;17).4,5

Of greatest clinical significance is the finding that in most patients the particular combination of antigens expressed by the leukemic cells may be rare or may never be seen in normal hematopoietic tissues. The more sophisticated immunophenotypic analyses have become, the more apparent it is that leukemic cells differ from normal hematopoietic cells and that leukemia categorization cannot be based solely on presumed normal counterparts. Of course, it is still valid to group the acute leukemias according to the major hematopoietic cell lineages (T-lymphoid, B-lymphoid, myeloid) and to distinguish between precursor and more mature subtypes based on the hierarchy of antigen expression observed in normal hematopoiesis. However, refined, clinically relevant subgroup-ing focuses increasingly on prognostically significant and/or therapy-determining features. The World Health Organization (WHO) classification of neoplastic diseases of the hematopoietic and lymphoid tissues clearly reflects this tendency by recognizing cytogenetic/molecular categories in the new nomenclature of the acute leukemias.6 It has become one of the major goals of leukemia immunobiology to identify antigens that can serve as surrogate markers of specific cytogenetic/molecular aberrations. The other major goal is to recognize leukemia-associated phenotypes that allow for the detection of immunologic residual disease. Monitoring of minimal residual disease has added a new dimension to leukemia immunophenotyping in addition to diagnosis and prognosis.

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