Multiple myeloma (MM) is a malignancy of plasma cells of the final maturation stage of B cells, characterized by atypical plasma cell proliferation in bone marrow and the production of monoclonal immunoglobulin. The history of chemotherapy for MM began in the early 1960s, when the efficacy of alkylating agents, particularly melphalan, was shown. High-dose therapy (HDT) has been the standard treatment for patients younger than 65 years since the superiority in terms of OS as well as PFS of HDT supported by autologous stem cell transplantation (ASCT) was reported. From the 2000s, the emergence of novel agents involving proteasome inhibitors such as bortezomib, and IMiDs such as thalidomide and lenalidomide, has been markedly changing MM treatment and improving the prognosis. As initial treatment, novel agents are frequently used since high response rates have been reported. For MM patients who are not candidates for HDT ASCT because of aging and/or organ dysfunction, combined therapies that consist of conventional chemotherapy and novel agents are usually recommended. The chromosomal aberrations frequently found in MM are 'hyperdiploid' or 'non-hyperdiploid' and immunoglobulin gene (Ig) translocation of chromosomes. It is known that the chromosomal aberration is associated with the treatment response and prognosis of MM patients, and this information is indispensable. Because chromosomal translocation is not readily detected by G banding, the FISH method is essential. In recent years, molecular mechanisms of MM have been revealed by microarrays (Gene Expression Profiles) and whole genome sequencing using next-generation sequencers. Furthermore, in-depth sequencing by such next-generation sequencers has revealed that MM is monoclonal, but shows intra-clonal heterogeneity at the onset of the disease from the viewpoint of genetic abnormality.

Multiple myeloma is one of incurable hematological malignancies and targeted therapies for novel oncogenes are to be exploited. Analyses of multiple myeloma patients revealed that HOXA9 was overexpressed in patients lacking known IgH translocation and it was evaluated as a candidate oncogene in multiple myeloma. This overexpression of HOXA9 was supposed to be due to dysfunction of histone methyltransferases (HMT) and mutations in MLL encoding HMT were found. Panobinostat, an HDAC inhibitor is currently undergoing preclinical and clinical evaluation as a novel drug for multiple myeloma. We found that panobinostat suppresses expression of MLL protein through modulation of its stability as well as Hsp90 inhibitor. More precise roles of MLL in pathogenesis of multiple myeloma are to be elucidated.

The tumor suppressor protein p53 is a multifunctional transcription factor involved in the control of cell survival and death. p53 is inactivated by mutation of the p53 gene in approximately 50% of human cancers. While the rest (including hematological malignancies) encode wild-type p53, p53 is frequently inhibited by its negative regulator human double minute 2 (HDM2). HDM2 is a p53-specific E3 ubiquitin ligase. Therefore, there has been considerable interest in identifying compounds for disrupting the p53-HDM2 interaction. Small-molecule antagonist of HDM2, which binds HDM2 in the p53-binding pocket, negatively controls the activity of HDM2 and prevents p53 degradation. This stabilization of p53 results in its activation, leading to cell cycle arrest, growth inhibition, and apoptosis in wild type p53-haboring hematological malignant cells. Biology of p53-HDM2 interaction and anti-tumor effects of the HDM2 inhibitor in hematological malignant cells are described in this review.

FLT3 is a class III receptor tyrosine kinase. FLT3 mutation is the most frequent genetic alteration in acute myeloid leukemia (AML), and involved in the signaling pathway of autonomous proliferation and differentiation block in leukemia cells. Since FLT3 mutation is strongly associated with leukocytosis and a poor prognosis, it is expected that development of FLT3 kinase inhibitors will make more efficacious therapeutic strategy for leukemia therapy. Although many FLT3 inhibitors have been subjected to clinical trials, their clinical efficacies for AML seem unimpressive, and several problems regarding adverse effects and resistant mechanism are apparent. Here, I would like to summarize recent advances of FLT3 inhibitors in development.

In recent years, recurrent somatic mutations in genes encoding proteins involved in DNA methylation and demethylation, and in histone modifications have been reported in myeloid malignancies. Large clinical correlative studies are beginning to clear the clinical importance, prevalence, and potential prognostic significance of these epigenetics modifying gene mutations. Additionally, recent studies shedding light on the role of epigenetics in the pathogenesis of myeloid malignancies has prompted increased interest in development of novel therapies which target DNA and histone posttranslational modifications. In this review, we summarize the current understanding of the epigenetics modifying gene mutation, discuss how contribute to its pathogenesis and clinical feature in AML.

The introduction of next generation sequencing technology has greatly broadened our view on the genetic landscape of hematological malignancies. The first comprehensive experiment of acute myeloid leukemia(AML) using genome-wide analysis has also shed light on the clonal evolution of AML, which seems to have been underestimated. It is now possible to precisely define clonal size and selection at different stages. This approach demonstrated that AML at diagnosis is either monoclonal or oligoclonal, harboring a selected number of genetically defined subclones. Furthermore, targeted deep sequencing of diagnosis and relapse pairs revealed that founding clones or subclones present at diagnosis obtain some additional mutations that contribute to clonal expansion and/or chemoresistance. Some subclones may be eradicated by treatment, whereas others are resistant to chemotherapeutic agents and ultimately grow out. The molecular heterogeneity in AML will have a great impact on the development of targeted therapies.

The next generation sequencing technologies has provided unprecedented opportunities for high-through-put genomic research. These technologies have been applied to hematological disorders in a variety of contexts and have provided genetic landscape of each disorder in details including the identification of disease specific driver mutations and subsequent chances of drug discovery targeting the pathogenetic lesions. On the other hand, the development of molecular targeted therapies has been successful in only limited fields to date. In this prospect we will review the current situation of molecular targeted therapy against several hematological diseases and discuss about the future challenges to promote drug discovery based on the enormous genomic information.

Promyelocytic crisis (PMC) of chronic myelogenous leukemia (CML) is relatively rare. We report a patient who progressed to PMC with a T315I mutation during the initial treatment with dasatinib for CML. He obtained hematological remission after combination therapy with all-trans retinoic acid and chemotherapy for PMC, and PML-RARA was not detected by FISH analysis. Arsenic trioxide (ATO) and imatinib therapy induced a second complete cytogenetic response, and PML-RARA mRNA detected by real-time quantitative RT-PCR dropped below the detection limit. Finally, allogeneic stem cell transplantation was performed. This case suggests that combination therapy with imatinib and ATO achieves favorable outcomes for PMC.

Herein, we report a patient with polycythemia vera (PV) who exhibited Philadelphia chromosome (Ph) positive CML-like clinical features after 13 years of hydroxycarbamide administration and successful treatment with a tyrosine kinase inhibitor (TKI). She was 64 years old when initially diagnosed with PV and was confirmed to be negative for BCR-ABL translocation. Thirteen years later, with increasing white blood cell and platelet counts, a BCR-ABL positive clone emerged and the JAK2V617F mutation disappeared. After TKI treatment, the BCR-ABL copy number decreased and the JAK2V617F mutation was again detected. Furthermore, MPN clinical features were observed. This case provides insights into the clonal divergence and growth advantage of the Ph positive clone over the MPN clone. Whether JAK2V617F is an MPN initiating event or a secondary mutation has been a point of discussion for the past several years. This issue is also considered in the present report.

Human cancers usually possess cumulative genetic aberrations. However, recent studies have revealed that the proliferation and survival of specific subsets of lung cancer depend on a few somatic mutation(s), so-called driver mutations. Representative driver mutations include the EGFR mutation and ALK translocation identified in about 40% and 3% of lung adenocarcinomas in Japan, respectively. These tumors are extremely sensitive to the respective tyrosine kinase inhibitors. This sensitivity has encouraged researchers and clinicians to explore novel driver mutations in lung cancers as future molecular targets. Driver mutations reported so far include the HER2 mutation, BRAF mutation, ROS1 translocation, RET translocation, and NTRK translocation in lung adenocarcinomas, and FGFR1 amplification, DDR2 mutation, and FGFR3 translocation in lung squamous cell carcinomas. However, despite initial dramatic responses, the acquisition of resistance to molecular targeted drugs is almost inevitable. Overcoming resistance to molecular targeted drugs, the key drugs at this time, is an urgent issue to improve the outcomes of lung cancer patients.

We describe a 76-year-old woman with cardiac tamponade who was admitted to our hospital. She underwent ascending and partial arch aortic replacement to treat acute type A aortic dissection. However, postoperative respiratory failure developed and a chest X-ray revealed right lung pneumothorax. The lung was finally expanded after difficulties with prolonged tube drainage. Chest computed tomography(CT) showed multiple cystic changes in the bilateral lungs. Her sister and her daughter also had a history of spontaneous pneumothorax. We finally diagnosed Birt-Hogg-Dube syndrome after deoxyribonucleic asid(DNA)sequencing of folliculin( FLCN) gene.

Somatic activating mutations such as a deletion in exon 19 or the missense mutation L858R in the tyrosine kinase domain of the epidermal growth factor receptor(EGFR)are important mediators of cancer cell oncogenesis, proliferation, and survival. In the last decade, two EGFR target agents have significantly contributed to the understanding of non-small cell lung cancer (NSCLC). Gefitinib and erlotinib are first-generation EGFR-tyrosine kinase inhibitors(EGFR-TKIs)that play a key role in activating EGFR-mutated NSCLC. Although these reversible, small, molecular target agents provide a significant response and survival benefit, all responders eventually acquire resistance. Although various mechanisms of resistance have been identified, nearly 3 0% of patients who acquire resistance to EGFR-TKIs have an unknown mechanism of resistance. Approximately half the patients with EGFR-mutated NSCLC who develop acquired resistance to these molecular target agents have a secondary mutation T790M in the threonine gatekeeper residue that coexists with a primary EGFR activating mutation. The strategy for overcoming acquired resistance to first-generation EGFR-TKIs is a major clinical concept. Afatinib is a second-generation EGFR-targeting agent and an irreversible pan-HER inhibitor. It may improve survival further and help in potentially overcoming resistance to first-generation EGFR-TKIs in EGFR-mutated NSCLC. In patients harboring activating EGFR mutations, certain treatments could be suggested for subsequent therapy after failure of first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for activating EGFR-mutated, advanced NSCLC after failure of first-generation EGFR-TKIs.

Apoptosis signal-regulating kinase 1 (ASK1) is a serine/threonine kinase belonging to the mitogen-activated protein kinase (MAPK) kinase kinase family. ASK1 is activated in response to various stresses, such as reactive oxygen species (ROS), tumor necrosis factor (TNF) alpha, lipopolysaccharide (LPS) and endoplasmic reticulum (ER) stress, and plays pivotal roles in a wide variety of cellular responses, including cell death, differentiation and inflammation. Recent studies have shown that ASK1-MAPK signaling pathway has key roles in human diseases induced by the dysfunction of cellular stress responses. In this review, we provide an overview of the current understanding of ASK1 as a potential therapeutic target for human diseases.

A 34-year-old man was referred to our hospital for leukocytosis and fundal hemorrhage. Peripheral blood and coagulation tests showed increases in cells at all stages of the neutrophilic series and a low level of fibrinogen (Fbg). Chronic myelogenous leukemia (CML) was diagnosed, and nilotinib was administered. During the clinical course of CML treatment, plasma Fbg levels continued to be low, but the patient showed neither hemorrhagic nor thrombotic complications. Fbg analysis showed normal antigen levels and low activity levels, which indicated dysfibrinogenemia. Genetic analysis revealed a heterozygous gene mutation (γ308AAT→AAG), a mutation which was also found in the patient's mother. Asymptomatic patients with dysfibrinogenemia have a low risk of hemorrhage in daily life and do not require treatment. However, in those undergoing major surgery or in serious accidents, replacement therapy may be required. When the cause of low Fbg levels is unknown, dysfibrinogenemia or fibrinogen deficiency should be considered. Even asymptomatic patients may benefit from more detailed immunologic and genetic analyses.

In a multicenter study, we evaluated the Major BCR-ABL mRNA/ABL mRNA quantification kit (M135R), which uses reference material included in the kit designed to report results using the international scale (IS). In total, 127 samples were studied. A good correlation was observed between M135R results and home-brew RT-qPCR results, which are reported on the IS using a conversion factor (r=0.90; n=115). However, the correlation coefficient between M135R results and Amp-CML results was relatively low (r=0.56; n=108). A good correlation was observed between M135R results from the two assay sites (r=0.94; n=115). The subset analysis of samples from the two assay sites showed M135R to have a good correlation even in the low IS range (r=0.98; IS≤1%). M135R showed high sensitivity and accuracy for detecting minimal residual disease and is considered to be a useful tool for treatment response assessment and for early detection of recurrence in CML patients.

Multiple myeloma (MM) develops and expands almost exclusively in the bone marrow, and generates devastating bone destruction. MM cells produce a variety of cytokines to stimulate RANK ligand-mediated osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. MM cells alter through bone destruction the microenvironment in bone where they colonize, which in turn favors tumor growth and survival, thereby forming a progressive vicious cycle between tumor expansion and bone destruction in MM.

Inorganic arsenic is a natural environmental contaminant and known to be a human carcinogen. Although rodent models are pivotal in elucidating the mode of action of arsenic, it has been difficult to verify the carcinogenicity of arsenic in rodents until recently. Waalkes et al. (Toxicol Appl Pharmacol 2003;
186:7-17) reported that maternal exposure to arsenite increases the incidence of hepatic tumors in the male pups of C3H mice in adulthood. This finding indicated that the gestational period is vulnerable to arsenic. Using the same experimental model, we found that maternal arsenite exposure increases the incidence of hepatic tumors caused by a somatic mutation of the C61A Ha-ras gene, which encodes an activated oncogenic Ha-ras protein. The G:C to T:A transversion is attributable to oxidative stress. Our further studies of gpt delta transgenic mice, which enable detection of in vivo mutation, and genome-wide analysis of DNA methylation levels using the methylated DNA immunoprecipitation-CpG island microarray method suggest that oxidative-stress-induced mutation and DNA methylation changes are involved in the tumor augmentation in the pups maternally exposed to arsenic. Our recent study has also suggested that maternal arsenic exposure increases the incidence of hepatic tumors even in the grandchildren (the F2 generation). Consideration should be given to multigenerational and transgenerational effects of maternal exposure in future studies.