Immunophenotyping of Acute Erythroid and Megakaryocyte Leukemia

There exists considerable overlap between the erythroid and megakaryocytic lineage at the gene as well as the protein level, both during normal development and in leukemic disorders.231-233'236'237'444'445 In terms of their immunophenotypic diagnosis, the lack of MPO expression by blast cells is the first indication of acute erythroid (AEL) or acute megakaryocytic leukemia (AMegL).

Acute Erythroid Leukemia

The majority of patients with AEL lack CD34 and HLA-DR expression.446 Despite the finding of glycophorin A as early as at the level of BFU-E,232 blasts in a fraction of AEL fail to react with antibodies to this most specific erythroid marker447,448 (Paietta E, unpublished observation). CD36 antibodies (to platelet glycoprotein IV), although strongly reactive with AEL cells446 will also stain megakaryocytic cells.233 The same is true for antibodies to blood group H antigen, the precursor structure of ABO blood group substances.449 Both these antigens, however, identify early stages of erythroid maturation, thereby increasing the odds of identifying a case of AEL. Blood group H antigen has also been demonstrated on leukemic blasts from patients with acute or chronic myelogenous leukemia.450 Myeloblasts and erythroblasts that are positive for blood group H antigen are distinguishable based on the myeloid antigens MPO or CD33, CD13, CD15, which are never, or rarely and selectively, expressed on erythroblasts, respectively.446 This differentiation is important because myeloblasts may constitute a significant component of the leukemic cell population in AEL.

Acute Megakaryocytic Leukemia

Antibodies to platelet-specific glycoproteins (GPIIb/IIIa [CD41/CD61], GPIb-GPIX [CD42], GPIV [CD36, GPIIIb]) are most valuable in characterizing MPO- acute leukemia as AMegL. If platelet peroxidase (PPO) activity, the enzymatic marker of megakaryocytic precursor cells,242 is detected by electron microscopy in more cells than are recognized as megakaryocytic by platelet GP expression,297 two explanations may apply. Either this finding reflects the appearance of PPO activity before platelet-specific GP during megakaryocytopoiesis,451 or it represents staining of PPO-like activity transiently present during early stages of normal and leukemic erythropoiesis.446 Therefore, surface marker analysis with platelet GP-specific antibodies is essential in the diagnosis of AMegL. The expression of GPIIIa or GPIIb/GPIIIa on CFU-MK,235,240 which lack PPO activity,242 implies that platelet GP analysis may not only be methodologically easier but also more specific and more sensitive than PPO studies. False-positive staining of AML blast cells with antiplatelet antibodies is due to the adhesion of platelets, possibly mediated by CD15, the ligand for P-selectin (CD62P) expressed on the cell surface of activated platelets452 (Paietta et al., unpublished). The platelet GPs CD41 and CD36 are expressed during erythropoiesis, but CD41 and to a lesser degree CD36 are restricted to early, HLA-DR+CD34- erythroid precursors, usually expressing CD71.231 In AMegL, CD41 is commonly associated with CD34, whereas CD36 is a late differentiation marker of CD34- megakaryocytic cells that also express CD42.233 The differential expression of CD41 (immature and mature) and CD42 (mature) on megakaryocytic cells is used to distinguish between promegakaryocytic CD41+ and megakaryoblastic CD41+CD42+ AMegL.453 The AMegL cells commonly express HLA-DR,453'454 CD34,454>455 and the early megakaryocytic antigens CD105 and CD109 (Paietta E, unpublished observation), suggesting their derivation from the promegakaryoblast or CFU-MK stage,240 which is consistent with their undifferentiated lymphoid-like appearance.242 Staining of subsets of cells in AMegL for the myeloid antigens CD33, CD13, or CD11b may represent a myeloblast component, particularly in cases in which megakaryocytic blasts account for less than 50 percent of leukemic cells, or may reflect coexpres-sion of platelet and myeloid antigens by the megakaryocytic blasts.454,455 The immunologic detection of micromegakary-ocytes in the peripheral blood of patients with myelofibrosis is indicative of AMegL,455,456 since megakaryoblasts produce and secrete an active form of transforming growth factor (TGF)-P, which promotes the synthesis of collagen in bone marrow fibroblasts.456

Expression of c-mpl, the thrombopoietin receptor, does not predict for AMegL457,458 (Paietta E, unpublished observation); this is comparable to the finding that it does not predict for commitment to the megakaryocytic lineage during normal hematopoiesis.232 Favorable cytogenetics in AML appear to correlate with lower levels of c-mpl protein.458 Inferior treatment responses have been seen in AML patients expressing c-mpl mRNA.457,459,460

The vast information provided today on detailed phenotypic profiles of leukemic cells using a multiparameter technological approach offers a chance to challenge conventional viewpoints on leukemogenesis by gaining novel insights into the origin and behavior of these malignant cells. As a result, our perspectives on the significance of characterizing acute leukemias according to immunobiological features may shift from the mere search for malignancy-associated qualitative phenotypic alterations to recognizing immunophenotyping as an essential source of information regarding the disruption of the specific regulatory circuits of cell proliferation and differentiation that lead to leukemia.

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