[Therapy-related leukemia].
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Antineoplastic Agents, Alkylating↗
Biomedical subjects
Tomoki Naoe
Publications and source records attributed to Tomoki Naoe.
Identification of a polymorphic gene, BCL2A1, encoding two novel hematopoietic lineage-specific minor histocompatibility antigens.
We report the identification of two novel minor histocompatibility antigens (mHAgs), encoded by two separate single nucleotide polymorphisms on a single gene, BCL2A1, and restricted by human histocompatibility leukocyte antigen (HLA)-A*2402 (the most common HLA-A allele in Japanese) and B*4403, respectively. Two cytotoxic T lymphocyte (CTL) clones specific for these mHAgs were first isolated from two distinct recipients after hematopoietic cell transplantation. Both clones lyse only normal and malignant cells within the hematopoietic lineage. To localize the gene encoding the mHAgs, two-point linkage analysis was performed on the CTL lytic patterns of restricting HLA-transfected B lymphoblastoid cell lines obtained from Centre d'Etude du Polymorphisme Humain. Both CTL clones showed a completely identical lytic pattern for 4 pedigrees and the gene was localized within a 3.6-cM interval of 15q24.3-25.1 region that encodes at least 46 genes. Of those, only BCL2A1 has been reported to be expressed in hematopoietic cells and possess three nonsynonymous nucleotide changes. Minigene transfection and epitope reconstitution assays with synthetic peptides identified both HLA-A*2402- and B*4403-restricted mHAg epitopes to be encoded by distinct polymorphisms within BCL2A1.
Amino Acid Sequence↗
The Japanese cord blood bank network experience with cord blood transplantation from unrelated donors for haematological malignancies: an evaluation of graft-versus-host disease prophylaxis.
Cryopreserved umbilical cord blood (CB) from unrelated donors can restore haematopoiesis after myeloablative therapy in patients with haematological malignancy. We investigated the clinical outcomes of CB transplantation (CBT) with special emphasis on graft-versus-host disease (GVHD) prophylaxis. Patients with haematological malignancies (n = 216) received intensive chemotherapy or immunosuppressive therapy, followed by transplantation of cryopreserved CB cells from unrelated donors. The clinical outcomes, i.e. haematological reconstitution, the incidence of acute or chronic GVHD, relapse and event-free survival (EFS), were evaluated. The estimated probability of neutrophil recovery was 88.2%. The median follow-up for the survivors was 557 d (range 21-1492 d). The overall and EFS rates were 32.6% and 25.5%, respectively, 3.5 years after transplantation. Multivariate analysis using Cox's proportional hazards model showed that high-risk disease status at CBT and single-drug GVHD prophylaxis were associated with worse 2-year EFS rates [P = 0.0013, relative risk (RR) 1.90, 95% confidence interval (CI) 1.28-2.81 and P = 0.0007, RR 1.91, 95% CI 1.31-2.79 respectively). Age at CBT had no significant influence on EFS. Cryopreserved CB from unrelated donors can restore haematopoiesis in patients with haematological malignancy. Although the incidence is low, the prophylaxis for acute GVHD is an important factor for survival of CBT from unrelated donors. A high rate of suitable donors was found, with a probability of 1 to every 18 CB units, when compared with human leucocyte antigen matching at other haematopoietic stem cell banks.
Acute Disease↗
Cord blood transplantation from unrelated donors: a preliminary report from the Japanese Cord Blood Bank Network.
As a source for hematopoietic stem cell transplantation (HSCT), cord blood transplantation from unrelated donors (UCBT) is now considered as an acceptable alternative to patients who need unrelated HSCT. To confirm the findings that mismatched UCBT is feasible, we discussed here the results for 477 patients with hematologic malignancies and non-malignancies who were subjected to UCBT coordinated by the Japanese Cord Blood Bank Network (JCBBN). From February 1997 to October 2001, 411 patients with malignancies and 66 with non-malignancies had UCBT through the cord blood bank in the JCBBN; 311 patients had HLA 0-1 mismatched UCBT; 165, had a 2-4 HLA mismatch. The Kaplan-Meier estimates for 3-year disease-free survival rate (DFS) were 35.2 +/- 2.8% in malignant diseases, and 33.6 +/- 7.2% in patients with non-malignant diseases. The HLA disparity had no effect on DFS, incidence of acute graft-versus-host disease, or engraftment. As reported previously, we also noted the importance of graft cell dose in determining survival in UCBT. Major advantages of UCBT include its rapid availability compared with unrelated donor bone marrow, and tolerance of an HLA mismatch at 2 loci, which will enable extension of the donor pool. This review outlines the latest UCBT progress, with emphasis on practical considerations in HLA-mismatched umbilical cord blood selection.
Adolescent↗
Antitumor effect of arsenic trioxide in murine xenograft model.
Arsenic trioxide, As(2)O(3) (ATO), has been established to be an effective agent for treating acute promyelocytic leukemia, but its effect on solid tumors has not been fully explored. In the present study in a murine xenograft system, we found that ATO significantly inhibited tumor growth of the inoculated human hepatocellular carcinoma cell line HuH7 when administered either intravenously or intratumorally. Pathological examination revealed that ATO induced extensive cell death in the tumor. Some of the dead cells in intratumorally ATO-treated mice showed characteristic features of apoptosis, such as nuclear condensation and fragmentation, and were TUNEL-positive. The measurement of arsenic by using particle induced X-ray emission revealed that arsenic was accumulated more in the tumor than in brain, kidney or liver after the intravenous injection of ATO, which is consistent with the hemorrhagic cell death observed in ATO-treated tumor tissues. Thus, ATO appears to have potential for the treatment of solid tumors, as well as hematopoietic malignancies.
Animals↗
Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain.
Internal tandem duplication (ITD) of the juxtamembrane (JM) domain of FLT3 is the most frequent mutation in human acute myeloid leukemia, and is significantly associated with leukocytosis and a poor prognosis. Previously we reported that FLT3 with ITD (FLT3/ITD) formed a homodimer and was autophosphorylated on tyrosine residues, while the mechanism remains unclear. In this study, we elucidated the role of the JM domain in FLT3 activation. Mutant FLT3 with not only ITD but also an elongating or shortening JM domain transformed murine IL3-dependent myeloid progenitor cell line 32D regardless of the tyrosine residues in the JM domain. These mutant FLT3s were constitutively tyrosine phosphorylated and activated signal-transduction molecules such as SHC, MAP kinase and STAT5a. Notably, co-transfection of the truncated FLT3/ITD lacking kinase and C-terminal domains with the wild type (Wt)-FLT3 into 32D cells resulted in the autonomous proliferation. In these cells, truncated FLT3/ITD generated a hetero-complex with Wt-FLT3 and Wt-FLT3 was constitutively tyrosine phosphorylated. These findings indicate that the FLT3 JM domain plays an important role in receptor activation, and that the length-mutated JM domain induces ligand-independent receptor activation but also activates Wt-FLT3 in a trans-manner.
Amino Acid Sequence↗
Arsenic trioxide-induced apoptosis through oxidative stress in cells of colon cancer cell lines.
Exposure of three colon cancer cell lines, SW480, DLD-1, and COLO201, to arsenic trioxide in the medium induced a marked concentration-dependent suppression of cell growth. The intracellular contents of reduced glutathione (GSH) in these cell lines tended to be inversely correlated with the sensitivity of the cells to arsenic trioxide. Among the cell lines, SW480 cells underwent apoptosis at the low arsenic trioxide concentration of 2 microM, which was prevented by pretreatment of the cells with N-acetylcysteine and was enhanced by buthionine sulfoximine. The production of reactive oxygen intermediates which were examined by 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA), increased with time after treatment with arsenic trioxide. The apoptosis was executed by the activation of caspase 3, which was shown by Western blot, enzymatic activity, and apoptosis inhibition assay. The mitochondrial membrane potential of adherent apoptotic SW480 cells and the cells from intermediate layer separated by density gradient centrifugation, both of which showed the active form of caspase 3 by Western blot analysis, was not lost. The overexpression of Bcl-2 protein in SW480 cells could not prevent the apoptosis induced by the treatment with arsenic trioxide. All these findings indicate that arsenic trioxide-induced apoptosis in SW480 cells is executed by the activation of caspase 3 without mediating by mitochondria under the overproduction of reactive oxygen species.
Antineoplastic Agents↗
Successful treatment with imatinib mesylate of a CML patient in megakaryoblastic crisis with severe fibrosis.
The prognosis of patients with chronic myeloid leukemia in blastic crisis (CML-BC) remains extremely poor, and multiagent chemotherapy regimens commonly used to treat acute leukemia offer only short-term benefits. Therefore, the advent of the novel molecularly targeted anticancer agent imatinib mesylate is a breakthrough in CML therapy. We present a CML patient in megakaryoblastic crisis with severe myelofibrosis, who was treated with imatinib at a dosage of 400 mg/day and achieved complete remission together with a marked regression of myelofibrosis after 1 month. The effect of imatinib on the long-term prognosis remains unclear, although the agent is clearly a promising drug for treating CML-BC even in cases of myelofibrosis.
Adult↗
FLT3 in human hematologic malignancies.
FLT3, a member of the receptor tyrosine kinase (RTK) class III, is preferentially expressed on the surface of a high proportion of acute myeloid leukemia (AML) and B-lineage acute lymphocytic leukemia (ALL) cells in addition to hematopoietic stem cells, brain, placenta and liver. An interaction of FLT3 and its ligand has been shown to play an important role in the survival, proliferation and differentiation of not only normal hematopoetic cells but also leukemia cells. Mutations of the FLT3 gene was first reported as an internal tandem duplication (ITD) of the juxtamembrane (JM) domain-coding sequence, subsequently as a missense mutation of D835 within a kinase domain. ITD- and D835-mutations are essentially found in AML and their frequencies are approximately 20 and 6% of adults with AML, respectively. Thus, mutation of the FLT3 gene is so far the most frequent genetic alteration reported to be involved in AML. Several large-scale studies in well-documented patients published to date have demonstrated that ITD-mutation is strongly associated with leukocytosis and a poor prognosis. In this review, we summarize the clinical and biological significance of FLT3-mutations and discuss the possibility of targeting FLT3 kinase for the treatment of leukemia.
Benzoquinones↗
Rapid screening of leukemia fusion transcripts in acute leukemia by real-time PCR.
We established a real-time PCR method that can simultaneously detect 10 different fusion transcripts (major, minor and micro BCR/ABL, AML1/MTG8, PML/RARalpha, CBFbeta/MYH11, TEL/AML1, E2A/PBX1, MLL/AF4, and MLL/AF9) together with Wilms' tumor gene (WT1) transcripts. This screening method allowed the processing of six specimens concomitantly and required only one working day from RNA extraction to final results. Fifty-seven bone marrow (BM) samples from patients with acute leukemia were retrospectively screened for the presence of fusion and WT1 transcripts without knowledge of the cytogenetic data, and the fusion transcripts were detected in 20 of 57 samples (35.1%). The concordance between the present method and cytogenetic analysis was examined in 38 samples in which the cytogenetic data were available. In 12 of 38 samples, the PCR results agreed with the cytogenetic data, whereas in 4 of the remaining 26 samples, the translocations were detected by real-time PCR alone because of the insufficient number of metaphases obtained and presumably the submicroscopic or masked translocations. The WT1 levels ranged from 400 to 690,000 copies/microg RNA in BM from leukemia patients, whereas 0-470 copies/microg RNA were found in BM cells from BMT donors. This real-time PCR method enables rapid and efficient characterization of acute leukemia in addition to subsequent evaluation of minimal residual diseases.
Acute Disease↗
GSTT1 and GSTM1 deletions, NQO1 C609T polymorphism and risk of chronic myelogenous leukemia in Japanese.
We conducted a prevalent case-control study with 51 chronic myelogenous leukemia (CML) cases and 476 controls to investigate the associations between glutathione S-transferase T1 (GSTT1), glutathione S-transferase M1 (GSTM1) deletions, and the NAD(P)H:quinone oxidoreductase 1 (NQO1) C609T polymorphism with risk of chronic myelocytic leukemia in Japanese. For the GSTT1 deletion, when the GSTT1 positive genotype was defined as the reference, the OR for the GSTT1 deletion genotype was 1.32 (95%CI; 0.74-2.36). For the GSTM1 deletion, when the GSTM1 positive genotype was defined as the reference, the OR for the GSTM1 deletion genotype was 0.95 (95%CI; 0.53-1.69). For NQO1 C609T polymorphism, when the NQO1 609CC genotype was defined as the reference, the ORs for the CT genotype, TT genotype, and CT and TT genotypes combined together were 2.37 (95%CI, 1.21-4.67, P=0.012), 1.44 (0.55-3.74, P=0.012) and 2.12 (1.10-4.08, P=0.025), respectively. The present study revealed that the risk of CML was modulated little by GSTT1 and GSTM1 deletions, but a statistically significant association between NQO1 C609T polymorphism and CML was observed for Japanese. Incidence case-control studies with a larger statistical power are now required to confirm our findings.
Adolescent↗