Acute Promyelocytic Leukemia

The immunophenotype of APL is unique and closely correlated with FAB-M3 and the cytogenetic hallmark of the disease, t(15;17)(q22;q11.2) and its molecular consequence, transcription of the PML/RARa fusion gene. Antigenic features of APL cells that correspond to those of normal promyelocytes are low expression of CD34, HLA-DR, the myelomonocytic antigens CD11b and CD14, and CD25.54 Atypical for promyelocytes is the predominant expression of CD15s54 and the coexpression of the monocyte-macrophage-associated antigens CD68 and CD9.379 Inconsistency in the literature data on CD15 expression by APL cells results from the variable reactivity patterns of the numerous available CD15 antibodies with the CD15s molecule.54,380 In the absence of CD34 and CD133, CD117 is a hallmark of APL, and CD117 is the ideal gating antibody for APL testing panels.18 A diagnostic finding is the absence of the leukocyte adhesion molecule CD11a on leukemic promyelo-cytes,18,381 which is otherwise ubiquitously found on the surface of myeloid leukemic cells with the exception of t(8;21) AML.18 Whenever present, CD34 and CD2 expression correlate with M3v morphology.12-14 Associations between immunophenotype, in particular CD2, and certain PML/RARa transcript forms382,383 and outcome383 have been suggested by some studies but not confirmed by others.54,384-386

The antigen profile of APL cells is similar to that of basophils (CD34-HLA-DR-CD15s+CD14-CD68+CD9+) which has prompted the hypothesis that APL cells may be derived from a basophil precursor cell.379 As is consistent with this idea, the presence of increased basophils in the bone marrow of some patients with APL,222 the existence of a rare hyperbasophilic form of APL,387'388 and the development of basophilia during induction therapy with ATRA,389 may reflect spontaneous or ATRA-induced terminal differentiation of the leukemic cells into basophils. On the other hand, APL cells and basophils differ immunophenotypically in that basophils express CD11b and CD25 but lack CD117.222,223

A lack of CD38379 in APL cells is not consistently observed. However, upregulation of CD38 expression by ATRA or arsenic trioxide may be the link between these two agents in the induction of the retinoic acid syndrome.42 The other potential culprit in the development of the syndrome is the aminopeptidase CD13.41 Expression of CD56 on the leukemic promyelocytes confers poor outcome in terms of overall survival22,23 and possibly achievement of complete remission.22

Acute promyelocytic leukemia cells characteristically express low levels of Pgp, at the mRNA level,390,391 the protein as well as the functional level.390,392 Lung resistance-related protein (LRP) and multidrug resistance-associated protein (MRP1) similarly show low expression in APL.392

Like normal myeloid precursors and most AML cells, APL cells are CD45RA-positive with low CD45R0 expression.63,381 In vitro treatment with ATRA decreases CD45RA while increasing the expression of CD45R0,63,381 which is consistent with progressive myeloid maturation.179 Further immunologic evidence for a dif-ferentiative process in vitro381 and in vivo393 is the ATRA-induced expression of CD11b on the previously CD11b-negative APL cells, a marker of mature granulomonocytic cells. Persistent absence of CD11a from these ATRA-induced CD15+ (no longer CD15s+)CD11b+ cells reflects incomplete differentiation.381 The term "intermediate cells" characterizes a stage during ATRA-induced differentiation at which the leukemic cells, which have lost their promyelocytic appearance, show strong staining for both CD33 and the mature myeloid antigen CD16.394 This staining pattern is not seen with normal CD16+ granulocytes, which weakly stain for CD33.62 Immunologically normal CD33lowCD16+ granulocytes, which appear subsequently when ATRA-treated APL patients achieve remission, represent the matured progeny of the leukemic clone as suggested by the presence of Auer rods and the demonstration of the t(15;17) in these cells.394

Recently, a rare variant of the APL immunophenotype has been recognized, which differs from classical APL only in the positive expression of CD11a and which lacks the (15;17) translocation.18 Given the exquisite sensitivity of APL to ATRA, it is essential to make every effort to correctly diagnose this disease.

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