Effects of DNA methyltransferase inhibitors (DNMTIs) on MDS-derived cell lines.

DNA methyltransferase inhibitors (DNMTIs), including decitabine (DAC) and azacitidine (AZA), have recently been highlighted for the treatment of high-risk myelodysplastic syndrome (MDS); however, their action mechanisms have not been clearly defined. Therefore, we investigated the effects of DNMTIs on MDS-derived cell lines in vitro. An MDS-derived cell line MDS92 and its blastic subline MDS-L and HL-60 were used. All three cell lines were sensitive to DNMTIs, but MDS-L was the most susceptible. DAC-induced cell death in MDS-L was preceded by DNA damage-induced G2 arrest via a p53-independent pathway. AZA did not influence the pattern of cell cycle, although it induced DNA damage response. The IC(50) of DAC or AZA on MDS-L cells was associated with the dose inducing the maximal hypomethylation in long interspersed nuclear elements-1 (LINE-1) methylation assay. AZA suppressed the level of methylation in a time-dependent manner (days 4, 7, and 10), whereas DAC maintained the level of methylation from day 4 to 11. The protein expression of DNMT1 and DNMT3a decreased with the suppression of growth and methylation. We conclude that this study provides in vitro models for understanding the effects of DNMTIs on cell growth and gene regulation, including differences in the possible action mechanism of DAC and AZA.

[Clinical analysis of eight patients with primary follicular lymphoma in the duodenum].

We performed a clinical analysis on 8 patients with primary follicular lymphoma in the duodenum taken from among 26 cases of primary gastrointestinal malignant lymphoma treated in our division. The median age was 60 years (range 48 to 82 yr). The ratio of males to females was 4:4. The chief complaints were no symptoms in 4 cases, heartburn in 2 cases, lower abdominal pain in 1 case, and back pain in 1 case. All patients were in clinical stage I EA. Gastroendoscopic findings showed multiple whitish granules around the ampulla of Vater in all patients. Involvement of the site in 6 cases was only located at the second portion; lesions in the other 2 cases were located at the second portion, and at the third portion or fourth portion, respectively. A histological study showed follicular lymphoma grade 1, and an immunohistological study demonstrated that the lymphoma cells were positive for CD79a, CD10, CD20, and bcl-2. Five patients were positive for the FISH analysis fusion signal of IgH/bcl-2 genes. Rituximab with CHOP therapy was performed for 7 patients. Seven patients are currently alive, and one died of uterine cancer. At the medium-term 39 month-follow-up, 7 patients were in complete remission, and 1 patient was in partial remission. Rituximab with CHOP (CVP) therapy is a possible treatment for primary follicular lymphoma in the duodenum. Further consideration of appropriate therapy for this disease might be necessary.

[A third complete remission of acute promyelocytic leukemia achieved by administering a gradual increase of all-trans retinoic acid following massive ascites due to retinoic acid syndrome].

A 69-year-old man was diagnosed as having acute promyelocytic leukemia (APL) and was treated with all-trans retinoic acid (ATRA) and idarubicin plus cytarabine. He achieved cytogenetic complete remission (CCR). Relapse occurred 1 year after CCR. Treatment with Am80 gave him a second CCR. However, a second relapse occurred. Re-induction therapy with ATRA was started at 70 mg per day. On day 14, abdominal fullness rapidly increased and massive ascites appeared as a symptom of retinoic acid syndrome (RAS). We ceased the ATRA treatment and started administration of methylprednisolone. The ascites decreased, but an increase of ascites was recognized again temporarily after having re-started ATRA treatment. Thus we gradually increased ATRA administration from 40 mg/day to 70 mg/day of ATRA. RAS did not occur and the patient achieved a third CCR. This case indicates that a gradual increase in ATRA administration is beneficial for RAS occurring in APL patients.

MLL/AF-1p fusion in therapy-related early pre-B acute lymphoblastic leukemia with t(1;11)(p32;q23) translocation developing in the relapse phase of acute promyelocytic leukemia.

We report the development of therapy-related early pre-B acute lymphoblastic leukemia in a patient administered a topoisomerase II inhibitor, etoposide, a consolidation therapy agent for acute promyelocytic leukemia. Our case is of interest because of simultaneous relapse of the original leukemia and onset of therapy-related leukemia and relatively rare t(1;11)(p32;q23) translocation with confirmed MLL/AF-1p fusion. This case suggests that careful monitoring for MLL gene rearrangements is necessary after administration of topoisomerase II inhibitors.