Our results demonstrated that imatinib-combined regimen is effective and feasible for newly diagnosed BCR-ABL-positive ALL. Despite a relatively short period of observation, a major potential of this treatment is recognized. Longer follow-up is required to determine its overall effect on survival.
Recently, somatic mutations of the nucleophosmin gene (NPM1), which alter the subcellular localization of the product, have been reported in acute myeloid leukemia (AML). We analyzed the clinical significance of NPM1 mutations in comparison with cytogenetics, FLT3, NRAS, and TP53 mutations, and a partial tandem duplication of the MLL gene (MLL-TD) in 257 patients with AML. We found NPM1 mutations, including 4 novel sequence variants, in 64 of 257 (24.9%) patients.NPM1 mutations were associated with normal karyotype and with internal tandem duplication (ITD) and D835 mutations in FLT3, but not with other mutations. In 190 patients without the M3 French-American-British (FAB) subtype who were treated with the protocol of the Japan Adult Leukemia Study Group, multivariate analyses showed that the NPM1 mutation was a favorable factor for achieving complete remission but was associated with a high relapse rate. Sequential analysis using 39 paired samples obtained at diagnosis and relapse showed that NPM1 mutations were lost at relapse in 2 of the 17 patients who had NPM1 mutations at diagnosis. These results suggest that the NPM1 mutation is not necessarily an early event during leukemogenesis or that leukemia clones with NPM1 mutations are sensitive to chemotherapy.
Our results show that age, hemorrhagic diathesis, and initial leukocyte count are prognostic factors for APL treated with ATRA followed by intensive chemotherapy.
Wilms' tumor 1 (WT1) is constantly expressed in leukemic cells of acute leukemia and myelodysplastic syndrome (MDS). A T-cell receptor (TCR) that specifically reacts with WT1 peptide in the context of HLA-A*24:02 has been identified. We conducted a first-in-human trial of TCR-gene transduced T-cell (TCR-T-cell) transfer in patients with refractory acute myeloblastic leukemia (AML) and high-risk MDS to investigate the safety and cell kinetics of the T cells. The WT1-specific TCR-gene was transduced to T cells using a retroviral vector encoding small interfering RNAs for endogenous TCR genes. The T cells were transferred twice with a 4-week interval in a dose-escalating design. After the second transfer, sequential WT1 peptide vaccines were given. Eight patients, divided into 2 dose cohorts, received cell transfer. No adverse events of normal tissue were seen. The TCR-T cells were detected in peripheral blood for 8 weeks at levels proportional to the dose administered, and in 5 patients, they persisted throughout the study period. The persisting cells maintained ex vivo peptide-specific immune reactivity. Two patients showed transient decreases in blast counts in bone marrow, which was associated with recovery of hematopoiesis. Four of 5 patients who had persistent T cells at the end of the study survived more than 12 months. These results suggest WT1-specific TCR-T cells manipulated by ex vivo culture of polyclonal peripheral lymphocytes survived in vivo and retained the capacity to mount an immune reaction to WT1. This trial was registered at www.umin.ac.jp as #UMIN000011519.
BACKGROUND The efficacy of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) from a human leukocyte antigen‐identical sibling donor remains controversial for patients with acute myeloid leukemia (AML) in first complete disease remission (CR1). Because the karyotype identified at diagnosis is the most relevant prognostic factor for AML, it should be possible to assess the efficacy more accurately on the basis of cytogenetic risk. METHODS The authors performed a metaanalysis of five studies, which employed both natural randomization based on donor availability and intention‐to‐treat analysis, with overall survival as an outcome of interest. Metaregression analysis was then performed to identify the efficacy for patients stratified into the favorable, intermediate, and poor cytogenetic risk groups. RESULTS For the entire cohort, there was a statistically significant advantage with allo‐HSCT in terms of overall survival with a summary hazard ratio of 1.15 (95% confidence interval, 1.01–1.32, P = 0.037) for the random‐effect model. Metaregression analysis showed a significant coefficient of +0.24 for the poor cytogenetic risk group, and −0.25 for the favorable cytogenetic risk group, indicating that the benefit of allo‐HSCT was further increased for the former, and lost for the latter. The coefficient for the intermediate cytogenetic risk group was +0.09, and was not statistically significant. CONCLUSIONS These findings suggested that the efficacy of allo‐HSCT for patients with AML in CR1 depended on cytogenetic risk. The beneficial effect of allo‐HSCT was yielded for the poor risk group, and probably for the intermediate risk groups, but was absent for the favorable risk group. Cancer 2005. © 2005 American Cancer Society.
We designed a novel type of cationic lipid, lipids with a cationic polar group in the polyamidoamine dendron, because these dendron-bearing lipids are expected to form complexes with plasmid DNA and achieve efficient transfection of cells by synergy of endosome buffering and membrane fusion with the endosome, both of which are useful for the promotion of the transfer of plasmid DNA from endosome to cytosol. Four kinds of lipids with polyamidoamine dendrons of first to fourth generations, DL-G1, DL-G2, DL-G3, and DL-G4, were synthesized. The lipid with a dendron of a higher generation exhibited greater ability to form lipoplexes with plasmid DNA, as estimated by agarose gel electrophoresis. While the DL-G1 lipoplex did not transfect CV1 cells, the lipoplexes containing the DL-G2, DL-G3, or DL-G4 could induce transfection of the cells, and their activity was elevated with increasing generation of the dendron. Addition of dioleoylphosphatidylethanolamine (DOPE), which is known to increase fusion ability of a lipid membrane, into the lipoplexes greatly enhanced their transfection activity. In addition, the comparison with DC-Chol-containing lipoplex, which is widely used as a nonviral vector, showed that the DL-G3-DOPE lipoplex exhibits more efficient transfections. These findings imply that these dendron-bearing lipids may form the basis for a novel family of cationic lipids for efficient gene delivery.
The TEL gene on 12p12-13 is a target for a number of translocations associated with various hematological malignancies. The fusion of the TEL gene to the Syk gene in a patient with myelodysplastic syndrome (MDS) with t(9;12)(q22;p12) is reported. Southern blot analysis of patient bone marrow cells with TEL and Syk gene probes detected rearranged fragments. Anchored polymerase chain reaction identified the Syk gene, a nonreceptor tyrosine kinase, on 9q22 fused downstream of TEL exon 5. The TEL gene was fused in-frame to Syk and produced a fusion protein that was constitutively phosphorylated in tyrosine with dimerization that was mediated by the helix-loop-helix domain of TEL. A TEL-Syk fusion product transformed the murine hematopoietic cell line BaF3 to interleukin-3 growth factor independence. TEL-Syk is a novel transforming protein and leads to the transformation of hematopoietic cells. These data implicate that the rearranged Syk gene is involved in the pathogenesis of hematopoietic malignancies.
The majority of acute promyelocytic leukemia (APL) cases are characterized by the presence of a promyelocytic leukemia-retinoic acid receptor alpha(RARA) fusion gene. In a small subset, RARA is fused to a different partner, usually involved in regulating cell growth and differentiation. Here, we identified a novel RARA fusion transcript, BCOR-RARA, in a t(X;17)(p11;q12) variant of APL with unique morphologic features, including rectangular and round cytoplasmic inclusion bodies. Although the patient was clinically responsive to all-trans retinoic acid, several relapses occurred with standard chemotherapy and all-trans retinoic acid. BCOR is a transcriptional corepressor through the proto-oncoprotein, BCL6, recruiting histone deacetylases and polycomb repressive complex 1 components. BCOR-RARA was found to possess common features with other RARA fusion proteins. These included: (1) the same break point in RARA cDNA; (2) selfassociation; (3) retinoid X receptor alpha is necessary for BCOR-RARA to associate with the RARA responsive element; (4) action in a dominant-negative manner on RARA transcriptional activation; and (5) aberrant subcellular relocalization. It should be noted that there was no intact BCOR found in the 45,-Y,t(X;17)(p11;q12) APL cells because they featured only a rearranged X chromosome. These results highlight essential features of pathogenesis in APL in more detail. BCOR appears to be involved not only in human congenital diseases, but also in a human cancer. IntroductionAcute promyelocytic leukemia (APL) is a distinct disease entity within the acute myelogenous leukemia (AML). [1][2][3] In the clinic, APL has characteristic morphologic features, including hypergranular promyelocytes, and exhibits a severe bleeding tendency, which is efficiently controlled with all-trans retinoic acid (ATRA) treatment. 4 The majority of APLs feature a balanced reciprocal translocation between chromosomes 15q22 and 17q12, which results in the fusion of the promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARA) genes. 5 In rare cases, other fusion partners of RARA are found, such as promyelocytic leukemia zinc finger (PLZF), 6 nucleophosmin (NPM1), 7 nuclear mitotic apparatus protein (NuMA), 8 signal transducer and activator of transcription 5b, 9 protein kinase A regulatory subunit type 1A, 10 and Fip1-like 1. 11 All of the RARA fusion proteins comprise all but the first 30 amino acids of RARA fused to a variable partner at its aminoterminus. [1][2][3] It is characteristic that all fusion partners have self-association domains. In the case of PML-RARA and PLZF-RARA, aberrant recruitment of transcriptional repressors, including nuclear corepressor protein/silencing mediator of retinoid and thyroid hormone receptor (NCOR/SMRT), histone deacetylases (HDACs), 12,13 and polycomb complexes, 14,15 to the retinoic acid responsive element (RARE) leads to ectopic repression of RAR target genes. 1,2 In mouse models of RARA fusion proteins, APL-like diseases occur after a long latency, presumably because of...
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