The malignant cells of acute promyelocytic leukemia (APL) contain a reciprocal chromosomal translocation that fuses the promyelocytic leukemia gene (PML) with the retinoic acid receptor ␣ gene (RAR␣). To test the hypothesis that the chimera PMLRAR␣ plays a role in leukemogenesis, we expressed a PMLRAR␣ cDNA in myeloid cells of transgenic mice. PMLRAR␣ transgenic mice exhibited impaired neutrophil maturation early in life, which progressed at a low frequency over the course of several months to overt APL. Both the preleukemic state and the leukemia could be transplanted to nontransgenic mice, and the transplanted preleukemia could progress to APL. The APL recapitulated features of the human disease, including a response to retinoic acid. Retinoic acid caused the leukemic cells to differentiate in vitro and in vivo, eliciting remissions of both the preleukemic state and APL in mice. Our results demonstrate that PML-RAR␣ impairs neutrophil differentiation and initiates the development of APL. The transgenic mice described here provide an apparently accurate model for human APL that includes clear evidence of tumor progression. The model should be useful for exploring the molecular pathogenesis of APL and the mechanisms of the therapeutic response to retinoic acid, as well as for preclinical studies of therapeutic regimens.The malignant cells of acute promyelocytic leukemia (APL) carry a reciprocal chromosomal translocation, t(15;17)(q24;q21) (1-3). The translocation fuses two genes (4, 5): RAR␣, which encodes the retinoic acid receptor ␣ (Rar␣); and promelocytic leukemia (PML), which encodes Pml, a nuclear phosphoprotein of unknown function (6). Prior to the identification of the genes at the t(15;17) breakpoint, all-trans retinoic acid (ATRA) had been shown to induce complete remission in APL patients by differentiation of the leukemic cells (7,8). This convergence of a novel therapeutic strategy and the molecular analysis of the translocation focused interest on how the resulting PMLRAR␣ and RAR␣PML fusion genes functioned in the pathogenesis and therapeutic response of APL.The PMLRAR␣ fusion encodes the bulk of both gene products. PmlRar␣ retains activities of both Pml and Rar␣, including transcriptional activation in response to retinoic acid, and can inhibit differentiation of cultured cells (5,(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). In contrast, the coding domain of the reciprocal RAR␣PML fusion contains little of note and has not been shown to have any phenotypic effects. While PMLRAR␣ is expressed in virtually all cases of APL, RAR␣PML is frequently not expressed (19). For these reasons it has been assumed that PMLRAR␣ is responsible for the initiation of leukemogenesis, but this view has not been directly authenticated.Here we report the establishment of a transgenic mouse model that documents the ability of PMLRAR␣ to initiate leukemogenesis. The mice develop two apparently unrelated abnormalities. The first is a severe papillomatosis of the skin that we will describe elsewhere. The second is a d...

Recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) has been reported to increase the leukocyte count in subhuman primates subjected to total-body irradiation and in patients with the acquired immunodeficiency syndrome. We administered this substance to 19 patients with breast cancer or melanoma treated with high-dose combination chemotherapy and autologous bone marrow support. Groups of three or four patients were treated with 2.0, 4.0, 8.0, 16.0, or 32.0 micrograms per kilogram of body weight per day of glycosylated rHuGM-CSF by continuous intravenous infusion for 14 days, beginning three hours after bone marrow infusion. Total leukocyte and granulocyte recovery was accelerated in these patients as compared with 24 historical controls matched for age, diagnosis, and treatment. Leukocyte counts (mean +/- SD) obtained 14 days after transplantation were 1511 +/- 1003 per microliter in patients given 2 to 8 micrograms per kilogram per day, 2575 +/- 2304 in those given 16 micrograms, and 3120 +/- 1744 in those given 32 micrograms, as compared with 863 +/- 645 per microliter in the controls. No consistent effect on platelet counts was noted. Toxic effects were generally mild and not clearly dose-related in patients given 2 to 16 micrograms per kilogram per day. Edema, weight gain, or myalgias occurred in all patients given 32 micrograms per kilogram; marked weight gain, generalized edema, pleural effusions, and hypotension developed in two patients, one of whom also had acute renal failure. Our results indicate that rHuGM-CSF can accelerate myeloid recovery after high-dose chemotherapy and autologous bone marrow transplantation, over a range of doses that can be tolerated. In this setting the ability to increase the dose is limited by the development of myalgias and fluid retention.

Myelodysplastic syndromes (MDS) and myeloproliferative syndromes (MPS) of childhood are a heterogeneous group of clonal disorders of hematopoiesis with overlapping clinical features and inconsistent nomenclature. Although a number of genetic conditions have been associated with MDS and MPS, the overall contribution of inherited predispositions is uncertain. We report a retrospective study examining clinical features, genetic associations, and outcomes in 167 children with MDS and MPS. Of these patients, 48 had an associated constitutional disorder. One hundred one patients had adult-type myelodysplastic syndrome (A-MDS), 60 had juvenile myelomonocytic leukemia (JMML), and 6 infants with Down syndrome had a transient myeloproliferative syndrome (TMS). JMML was characterized by young age at onset and prominent hepatosplenomegaly, whereas patients with A-MDS were older and had little or no organomegaly. The most common cytogenetic abnormalities were monosomy 7 or del(7q) (53 cases); this was common both in patients with JMML and those with A-MDS. Leukemic transformation was observed in 32% of patients, usually within 2 years of diagnosis. Survival was 25% at 16 years. Favorable prognostic features at diagnosis included age less than 2 years and a hemoglobin F level of less than 10%. Older patients tended to present with an adult-type MDS that is accommodated within the French-American-British system. In contrast, infants and young children typically developed unique disorders with overlapping features of MDS and MPS. Although the type and intensity of therapy varied markedly in this study, the overall outcome was poor except in patients with TMS.