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ABSTRACr A human leukemic cell line (designated H-1O0) has recently been established from the peripheral blood leukocytes of a patient with acute promyelocytic leukemia. This cell line displays distinct morphological and histochemical commitment towards myeloid differentiation. The cultured cells are predominantly promyelocytes, but the addition of dimethyl sulfoxide to the culture induces them to differentiate into myelocytes, metamyelocytes, and banded and segmented neutrophils. All 150 clones developed from the HLAO culture show similar morphological differentiation in the presence of dimethyl sulfoxide. Unlike the morphologically immature promyelocytes, the dimethyl sulfoxide-induced mature cells exhibit functional maturity as exemplified by hagocytic activity. A number of other compounds previously shown toinduce erythroid differentiation of mouse erythroleukemia (Friend) cells can induce analogous maturation of the myeloid HL-60 cells. The marked similarity in behavior of HL-O0 cells and Friend cells in the presence of these inducing agents suggests that similar molecular mechanisms are involved in the induction of differentiation of these human myeloid and murine erythroid leukemic cells. mented neutrophils. Although conditioned medium from a whole human embryo fibroblast strain was apparently required to initiate growth of the HL-60 cells (11), these cells, unlike human myeloid cells in our previous experience (12-14), do not require exogenous factor or conditioned medium for sustained growth. The cells have continuously proliferated and maintained distinct myeloid characteristics for over a year in suspension culture. Their morphological and histochemical myeloid characteristics are similar to those of the patient's uncultured leukemic blood cells, and the modal chromosome number of 44 found in the early passages of the HL-60 culture is the same as the modal chromosome number observed in fresh bone marrow obtained from the patient prior to chemotherapy (11). These findings, together with the ability of the cultured HL-60 cells to be tumorigenic in athymic nude mice (to be published elsewhere), indicate that the HL-60 cells are leukemic in origin.In the present study we show that after the addition of MeaSO and other polar compounds capable of inducing maturation in the above-mentioned rodent cell lines, there is a marked increase in the proportion of mature myeloid cells in the human HL-60 culture. Moreover, these morphologically mature cells, unlike the immature promyelocytes, are now capable of phagocytosis. Thus a differentiation-inducing effect of Me2SO and related compounds has now been demonstrated in human cells. The fact that these compounds can induce differentiation in such a variety of different rodent and human cell lines suggests that they may trigger differentiation through common mechanisms in a wide range of mammalian cells. MATERIALS AND METHODS

Arsenic trioxide (As 2 O 3 ) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age > 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As 2 O 3 consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As 2 O 3 consolidation, 80% compared with 63% at 3 years (stratified logrank test, P < .0001). Survival, a secondary end point, was better in the As 2 O 3 arm, 86% compared with 81% at 3 years (P ‫؍‬ .059). Disease-free survival, a secondary end point, was significantly better in the As 2 O 3 arm, 90% compared with 70% at 3 years (P < .0001). The addition of As 2 O 3 consolidation to standard induction and consolidation therapy significantly improves event-free and diseasefree survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934).

The HL-60 human promyelocytic leukemia cell line can be induced to terminally differentiate to mature myeloid cells sharing a number of functional characteristics with normal granulocytes including response to chemoattractants, development of complement receptors, phagocytosis, superoxide production, and nitroblue tetrazolium dye reduction. Hence the Me2SO-induced HL-60 cells provide a unique in vitro model for studying various important aspects of human myeloid cell differentiation.