Natural Killer (NK) cells are critical in host defense against malignant transformation and are potent antileukemic cytotoxic effectors. In the present study, we investigated the peripheral NK function in patients with myelodysplastic syndromes (MDS). We demonstrated that the peripheral NK cell population was quantitatively normal in MDS patients. Furthermore, NK cells displayed an expression of the activating natural cytotoxicity receptors (NCR) NKp46 and NKp30 as well as NKG2D similar to that observed in donors, but exert a highly decreased constitutive cytolytic activity compared to resting normal NK cells. Although activation with IL-2 resulted in the upregulation of NKp46 expression by MDS-NK cells, their cytolytic function remained deeply altered as compared to activated donor NK cells. In addition, MDS NK cells did not proliferate in vitro, and displayed an increased rate of apoptosis in response to IL-2 stimulation although the spontaneous apoptosis was not significantly increased. Interestingly, a proportion of peripheral MDS-NK cells were derived from the MDS clone as the cytogenetic anomaly found in bone marrow karyotype was also detected in 20-50% of circulating NK cells. In conclusion, NK cells' cytolytic function and proliferative capacities in response to activation by cytokines are profoundly altered in MDS.

With improved treatment of acute promyelocytic leukemia (APL) by all trans retinoic acid (ATRA) combined to anthracycline-aracytin chemotherapy (CT), a larger number of those patients may be at risk of late complications. Recently, the Rome group reported five cases of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML, non-APL) occurring during the course of 77 APL patients (6.5%) in complete remission (CR). From 1991 to 1998, we treated 677 newly diagnosed cases of APL, and 617 of them achieved CR with ATRA combined to CT (n ¼ 579) or CT alone (n ¼ 38); 246 of them received subsequent maintenance CT with 6 mercaptopurine and methotrexate. With a median follow-up of 51 months, 6 patients (0.97%) developed MDS, 13-74 months after the diagnosis of APL. In all six cases, t(15;17) and PMLRARalpha rearrangement were absent at the time of MDS diagnosis, and karyotype mainly showed complex cytogenetic abnormalities involving chromosomes 5 and/or 7, typical of MDS observed after treatment with alkylating agents, although none of the six patients had received such agents for the treatment of APL. Our findings suggest that MDS can indeed be a long-term complication in APL, although probably at lower incidence than that previously reported. Leukemia (2003) 17, 1600-1604. doi:10.1038/sj.leu.2403034 Keywords: acute promyelocytic leukemia-myelodysplastic syndrome; therapy related Introduction Acute promyelocytic leukemia (APL) is a specific type of acute myeloid leukemia (AML) characterized by the morphology of blast cells (M3 according to FAB classification), t(15;17) translocation that fuses the PML gene on chromosome 15 to the RAR alpha gene on chromosome 17, and by specific coagulopathy. 1,2 Anthracycline-aracytin (AraC) chemotherapy (CT), introduced in the 1960s, has yielded cure rates of 35-40% in APL, whereas combination of anthracycline-Ara C or anthracycline alone CT to all trans retinoic acid (ATRA), introduced in the early 1990s, has improved this cure rate to 65-70%, 3-6 thereby increasing the number of patients potentially at risk of late side effects of treatments. In the last 2 years, several case reports of myelodysplastic syndrome (MDS) or AML (different from APL), occurring during the course of APL, have been made. Recently, the Rome group 7 reported five cases of MDS in 77 (6.5%) APL patients treated with CT alone or ATRA combined to CT, suggesting that MDS/AML was possibly a major emerging problem in the follow-up of APL. Those findings prompted us to review cases of MDS or AML (non-APL) occurring during the evolution of APL patients included in multicenter trials of our European group. Patients and treatment PatientsBetween 1991 and 1998, we included 677 newly diagnosed cases of APL in APL 91 and APL 93 trials. Inclusion criteria were: diagnosis of APL based on morphological criteria and subsequently confirmed by presence of t(15;17) or PML-RAR alpha gene rearrangement, 8 age 75 years or less, and a minimum follow-up of 3 years.Treatment 9-11 APL 91 trial design: Patients were randomized to re...