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Since the introduction of all- trans retinoic acid (ATRA) and arsenic trioxide (As 2 O 3 ) for the treatment of acute promyelocytic leukemia (APL), the overall survival rate has improved dramatically. However, relapse/refractory patients showing resistance to ATRA and/or As 2 O 3 are recognized as a clinically significant problem. Genetic mutations resulting in amino acid substitution in the retinoic acid receptor alpha (RARα) ligand binding domain (LBD) and the PML-B2 domain of PML-RARα, respectively, have been reported as molecular mechanisms underlying resistance to ATRA and As 2 O 3 . In the LBD mutation, ATRA binding with LBD is generally impaired, and ligand-dependent co-repressor dissociation and degradation of PML-RARα by the proteasome pathway, leading to cell differentiation, are inhibited. The PML-B2 mutation interferes with the direct binding of As 2 O 3 with PML-B2, and PML-RARα SUMOylation with As 2 O 3 followed by multimerization and degradation is impaired. To overcome ATRA resistance, utilization of As 2 O 3 provides a preferable outcome, and recently, a synthetic retinoid Am80, which has a higher binding affinity with PML-RARα than ATRA, has been tested in the clinical setting. However, no strategy attempted to date has been successful in overcoming As 2 O 3 resistance. Detailed genomic analyses using patient samples harvested repeatedly may help in predicting the prognosis, selecting the effective targeting drugs, and designing new sophisticated strategies for the treatment of APL.

Recently, it has been found that inappropriate expression of microRNAs (miRNAs) is strongly associated with carcinogenesis. In this study, we demonstrated that the expression of miRNAs (miRs) ‐143 and ‐145, the levels of which were previously shown to be reduced in colon cancers and various kinds of established cancer cell lines, was also decreased in most of the B‐cell malignancies examined, including chronic lymphocytic leukemias (CLL), B‐cell lymphomas, Epstein‐Barr virus (EBV)‐transformed B‐cell lines, and Burkitt lymphoma cell lines. All samples from 13 CLL patients and eight of nine B‐cell lymphoma ones tested exhibited an extremely low expression of miRs‐143 and ‐145. The expression levels of miRs‐143 and ‐145 were consistently low in human Burkitt lymphoma cell lines and were inversely associated with the cell proliferation observed in the EBV‐transformed B‐cell lines. Moreover, the introduction of either precursor or mature miR‐143 and ‐145 into Raji cells resulted in a significant growth inhibition that occurred in a dose‐dependent manner and the target gene of miRNA‐143 was determined to be ERK5, as previously reported in human colon cancer DLD‐1 cells. Taken together, these findings suggest that miRs‐143 and ‐145 may be useful as biomarkers that differentiate B‐cell malignant cells from normal cells and contribute to carcinogenesis in B‐cell malignancies by a newly defined mechanism. (Cancer Sci 2007; 98: 1914–1920)

Acute myeloid leukemia (AML) is predominantly a disease of older adults, with a median age at diagnosis of over 65 years. AML in older adults differs biologically and clinically from that in younger ones, and is characterized by stronger intrinsic resistance and lower tolerance to chemotherapy. The effects of age on both patient- and disease-related factors result in a higher incidence of early death during chemotherapy, a lower rate of complete remission, and a reduced chance of long-term survival. Treatment options for older adults with AML include intensive chemotherapy, less-intensive chemotherapy, best supportive care, or enrolment in clinical trials. Given the heterogeneous nature of AML in older adults, therapeutic decisions need to be individualized after systematic assessment of disease biology and patient characteristics. Regardless of treatment, however, outcomes for older AML patients remain in general unsatisfactory. In contrast with the progress made for younger adults, the treatment of AML in older adults has not improved significantly in recent decades. Development of less toxic and more targeted agents may well provide treatment alternatives for a majority of these patients. The overall dismal outcome with currently available treatment approaches has encouraged older AML patients to participate in prospective clinical trials.

Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity of non-Hodgkin lymphoma according to the current WHO classification. This rare form of B-cell lymphoma is characterised by selective growth of tumour cells in the lumina of small vessels of various organs. Strange characteristics of IVLBCL, including the absence of marked lymphoadenopathy and the usually aggressive clinical behaviour, result in the delay of timely and accurate diagnosis and fatal complications. Thus, the prognosis of IVLBCL is extremely poor. The success achieved with the anti-CD20 chimeric monoclonal antibody, rituximab, represents an important milestone in the clinical practice of B-cell lymphoma. An advantage of adding rituximab to conventional chemotherapies has been shown, in the process of increasing our understanding of the clinical and pathological manifestations for IVLBCL. This Review describes the cutting edge of research on IVLBCL, and discusses the unsolved issues from biological and clinical perspectives to provide a better understanding of this rare lymphoma.

Aberrant activation of the Hedgehog signaling pathway has been implicated in the maintenance of leukemia stem cell populations in several model systems. PF‐04449913 (PF‐913) is a selective, small‐molecule inhibitor of Smoothened, a membrane protein that regulates the Hedgehog pathway. However, details of the proof‐of‐concept and mechanism of action of PF‐913 following administration to patients with acute myeloid leukemia (AML) are unclear. This study examined the role of the Hedgehog signaling pathway in AML cells, and evaluated the in vitro and in vivo effects of the Smoothened inhibitor PF‐913. In primary AML cells, activation of the Hedgehog signaling pathway was more pronounced in CD34+ cells than CD34− cells. In vitro treatment with PF‐913 induced a decrease in the quiescent cell population accompanied by minimal cell death. In vivo treatment with PF‐913 attenuated the leukemia‐initiation potential of AML cells in a serial transplantation mouse model, while limiting reduction of tumor burden in a primary xenotransplant system. Comprehensive gene set enrichment analysis revealed that PF‐913 modulated self‐renewal signatures and cell cycle progression. Furthermore, PF‐913 sensitized AML cells to cytosine arabinoside, and abrogated resistance to cytosine arabinoside in AML cells cocultured with HS‐5 stromal cells. These findings imply that pharmacologic inhibition of Hedgehog signaling attenuates the leukemia‐initiation potential, and also enhanced AML therapy by sensitizing dormant leukemia stem cells to chemotherapy and overcoming resistance in the bone marrow microenvironment.

Microvesicles (MVs) and exosomes, which are shed from cells as a cell-to-cell communication tool, are possible vehicles for navigating RNA molecules to body tissues. It is considered that intravenous injection of such MVs or exosomes from patients would not cause severe not-self and toxic reactions. Previously, we found that macrophages take up liposome-entrapped RNA molecules, some of which remain undegraded in the cells. Here, we demonstrate that transfected RNA molecules in human monocytic leukemia THP-1 cells were shed from THP-1 macrophages as contents in MVs during incubation in serum-free medium, which shedding was shown by biochemical analyses such as quantitative reverse transcription (qRT)-PCR, expression of TSG101 (a membrane-associated exosomal protein), and immunoelectron microscopic study. More chemically modified RNA molecules (miR-143BPs) entrapped by MVs (MV-miR-143BPs) were secreted from THP-1 macrophages after miR-143BP transfection compared with the amount after transfection with nonmodified miR-143 transfection. Furthermore, we show that the THP-1 macrophages, which were transfected with the miR-143BP ex vivo, secreted MV-miR-143BPs in xenografted nude mice after intravenous injection, because miR-143 levels were significantly increased in the serum, tumor, and kidney of the host animals. These data suggest that some of the transfected miR-143BPs were secreted from THP-1 macrophages as MV-RNAs both in vitro and in vivo.

Hiroyuki Mano and colleagues report fusions involving DUX4 in 16.4% of Ph-negative adolescent and young adult acute lymphoblastic leukemia (AYA-ALL) cases. Transplantation assays in mice support an oncogenic role for the DUX4-IGH fusion gene, which expresses DUX4 protein with an aberrant C terminus at high levels in patients with AYA-ALL. The oncogenic mechanisms underlying acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA; 15–39 years old) remain largely elusive 1 , 2 , 3 . Here we have searched for new oncogenes in AYA-ALL by performing RNA-seq analysis of Philadelphia chromosome (Ph)-negative AYA-ALL specimens ( n = 73) with the use of a next-generation sequencer. Interestingly, insertion of D4Z4 repeats containing the DUX4 gene into the IGH locus was frequently identified in B cell AYA-ALL, leading to a high level of expression of DUX4 protein with an aberrant C terminus. A transplantation assay in mice demonstrated that expression of DUX4 - IGH in pro-B cells was capable of generating B cell leukemia in vivo . DUX4 fusions were preferentially detected in the AYA generation. Our data thus show that DUX4 can become an oncogenic driver as a result of somatic chromosomal rearrangements and that AYA-ALL may be a clinical entity distinct from ALL at other ages.

Ten years ago, gene mutations found in acute myeloid leukemia (AML) were conceptually grouped into class I mutation, which causes constitutive activation of intracellular signals that contribute to the growth and survival, and class II mutation, which blocks differentiation and/or enhance self-renewal by altered transcription factors. A cooperative model between two classes of mutations has been suggested by murine experiments and partly supported by epidemiological findings. In the last 5 years, comprehensive genomic analysis proceeded to find new gene mutations, which are found in the epigenome-associated enzymes and the molecules never noticed so far. These new mutations apparently increase the complexity and heterogeneity of AML. Although a long list of gene mutations might have been compiled, the entire picture of molecular pathogenesis in AML remains to be elucidated because gene rearrangement, gene copy number, DNA methylation and expression profiles are not fully studied in conjunction with gene mutations. Comprehensive genome research will deepen the understanding of AML to promote the development of new classification and treatment. This review focuses on gene mutations that were recently discovered by genome sequencing.

Nucleophosmin (NPM1) is a multifunctional phosphoprotein which plays important roles in diverse biological processes. NPM1 can form homo- or hetero-oligomers through its N-terminal region, and bind DNA and RNA through its C-terminal region. However, the monomer-oligomer distribution of NPM1, and the extent of NPM1 binding and unbinding to RNA in living cells, are not fully understood. In this work, we analysed molecular complexes of NPM1 using size exclusion chromatography. We found that a substantial fraction of NPM1 behaves as an oligomer in HeLa cells. Furthermore, we identified three distinct oligomeric states of NPM1 using molecular characterization techniques such as subcellular localization and RNA binding. Finally, we found that heterozygous expression of a leukemia-associated NPM1 mutant significantly decreases the RNA binding level. Our data demonstrate that size exclusion chromatography provides a powerful tool for analysing NPM1 oligomers.