Acute promyelocytic leukemia (APL) is one of the well-characterized subtypes of acute myeloid leukemia (AML). The essential drugs used in the treatment strategy for APL include all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which are both pioneer molecular-targeting agents. They were initially administered to patients based on the therapeutic experience of traditional Chinese medicine, and their marked effectiveness has been demonstrated. Subsequently, the molecular mechanisms of these drugs, as well as the molecular pathogenesis of APL, have been elucidated, whereby the chimeric gene product PML-RARα induces epigenetic changes and transcription repression. This review summarizes the findings of previous studies related to the in vitro and in vivo function of PML-RARα and the effects of ATRA and ATO on PML-RARα and APL cells. These findings are very important, because the concept of epigenetic modulation in oncogenesis and their application as molecular targets in APL therapy have now been accepted in other types of leukemia, as well as for other malignancies.

Generally, hematological malignancies are morphologically diagnosed and classified. However, since their clinical characteristics are markedly heterogeneous, routinely used classification systems are not necessarily useful for the benefit of patients. Recent progress in the detection system for genetic alterations has revealed several mutations, which are associated with the development and/or progression of hematological malignancies, and the accumulation of data on the prognostic significance of recurrent genetic alterations has made more detailed risk stratification possible in patients with hematological malignancies. In acute myeloid leukemia (AML), prognostic risk classification based on cytogenetics has been established, while there is a clinical heterogeneity in the intermediate risk group, particularly in those with cytogenetically normal AML. The European LeukemiaNet (ELN) recommended a novel risk classification system based on the cytogenetic and genetic status. The long-term prognosis according to the ELN classification system was retrospectively evaluated in two well-established cohorts, and both analyses demonstrated that the ELN system is useful for further risk stratification of younger adult patients with CN-AML. A genetic diagnosis and classification system will provide important information for both patients and physicians, while the overall picture of molecular pathogenesis in hematological malignancies remains to be elucidated.

The fecal occult blood test (FOBT) is widely used for colorectal cancer (CRC) screening to reduce the mortality rate associated with this cancer. However, several problems exist, as FOBT results can contain some false-negative CRC patients and some-false positive healthy subjects. Thus, to resolve these problems, several fecal biomarkers based on fecal protein, fecal DNA, and fecal RNA have been reported. Fecal calprotectin, which indicates intestinal bleeding or inflammation of the colon mucosa, and fecal tumor M2-PK, which is produced by cancer cells, have been extensively investigated as fecal protein biomarkers. To detect small amounts of CRC-specific proteins, the chemiluminescent enzyme immunoassay (CLEIA), which is a highly sensitive protein detection method using immunomagnetic beads, will be used. DNA mutation of APC, KRAS, and TP53 genes and DNA methylation of VIM, TFPI2, BMP3, NDRG4, and SFRP2 genes were reported as fecal DNA biomarkers. Consequently, a fecal DNA test named Cologuard from Exact Sciences was approved by the FDA in August 2014. Fecal COX2, MMP7, miR-106a, miR-92a, and miR-223 were also reported as fecal RNA biomarkers. This review article summarizes fecal biomarkers using fecal samples for CRC diagnosis.

Alternative splicing is a fundamental process of gene regulation that contributes to protein diversity, a common phenomenon in the mammalian genome. Alternative splicing events not only happen in the normal gene regulation process, but are also closely related to certain diseases, including cancer. In this review, we briefly demonstrate the proof of concept (POC) of the relationship between alternative splicing and DNA damage, and describe the associations among alternative splicing and cancer pathogenesis, DNA damage, and gastrointestinal cancers. We discuss whether alternative splicing leads to genetic instability, which is considered to be a driving force for tumorigenesis. FUSE-binding protein (FBP) -interacting repressor (FIR) is a c-myc transcriptional suppressor. A splice variant of FIR that lacks exon 2 in the transcriptional repressor domain (FIRΔexon2), upregulates c-myc transcription by inactivating wild-type FIR. FIR+/- mice exhibited marked c-myc mRNA upregulation, particularly in the peripheral blood (PB), without any significant pathogenic phenotype. Because the single knockout of TP53 generates thymic lymphoma, FIR+/-TP53-/- mice developed T-cell type acute lymphocytic/lymphoblastic leukemia (T-ALL) with increased organ or bone marrow invasion and showed a poor prognosis. After describing the POC of alternative splicing of FIR in DNA damage and carcinogenesis, clinical application for cancer diagnosis and treatment by FIR/FIRΔexon2 was briefly summarized. Chiba University has prepared a biobank to support studies to develop biomarker detection, molecular diagnosis, and "Omics" research. In conclusion, alternative splicing of FIR, generating FIRΔexon2, potentially contributes to not only colorectal carcinogenesis, but also leukemogenesis, and a better understanding of the role and mechanism of alternative splicing in tumorigenesis may reveal new directions for cancer biomarker detection.

Cetuximab has shown efficacy in patients with metastatic colorectal cancer (mCRC). Recent studies have demonstrated that cetuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC), mediated via the fragment c gamma receptors(FcgR)in mCRC. Since the establishment of KRAS mutations as a major negative predictor of efficacy, additional biomarkers have been found to be useful for the improvement of selection of patients likely to be responsive to cetuximab. We investigated the relationship between polymorphisms and the outcome of mCRC patients treated with cetuximab.

A 65-year-old woman underwent iliocecal resection for cecal cancer. During post-operative follow-up, she was diagnosed with metastasis to the abdominal wall and a curative resection was performed. After 12 courses of adjuvant chemotherapy with a modified combination of folinic acid, 5-fluorouracil, and oxaliplatin (mFOLFOX6), recurrence was noted in the lung. A curative resection was successfully performed and she was subsequently treated with bevacizumab and a combination of folinic acid, 5-fluorouracil, and irinotecan (FOLFIRI). One year after surgical resection, recurrence in the remnant lung was diagnosed. Because of the KRAS mutation, she could not be treated with anti-epidermal growth factor antibodies. The metastatic lung tumor continued to enlarge. Therefore, we selected regorafenib as third-line chemotherapy. After treatment with regorafenib, the size of the target lesion decreased significantly.

Adoptive T-cell therapy using chimeric antigen receptor (CAR) technology is a novel approach to cancer immuno-gene therapy. CARs are hybrid proteins consisting of a target-antigen-specific single-chain antibody fragment fused to intracellular T-cell activation domains (CD28 or CD137/CD3ζ receptor). CAR-expressing engineered T lymphocytes can directly recognize and kill tumor cells in an HLA independent manner. In the United States, promising results have been obtained in clinical trials of adoptive immuno-gene therapy using CD19-CAR-T lymphocytes for the treatment of refractory B-cell malignancies, including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and malignant lymphoma.

Specific chromosomal abnormalities are of diagnostic and prognostic relevance as well as providing clues for the identification of causative genes in patients with hematological malignancies. Genomic array (GA) is a powerful tool for identifying both microdeletion and precise DNA breakpoints in the genes of interest. For example, GA was able to detect CDKN2A and CDKN2B deletions in a small region only 69kb in size at 9p21 that were frequently found in patients with double-hit lymphoma. Using GA combined with spectral karyotyping, fluorescence in situ hybridization, and RT-PCR, we have identified a novel PVT1 rearrangement at 8q24 which were partnered with NBEA and WWOX in multiple myeloma (MM). In patients with MM, NBEA and WWOX are frequently involved in chromosomal deletion at 13q14 and 16q23, respectively. In acute myeloid leukemia, novel fusion RNAs, PVT1-NSMCE2 and CCDC26-NSMCE2, were identified in association with marker chromosomes and double minute chromosomes derived from chromosome 8 showing 8q24 amplicons. Chromothripsis is a possible cytogenetic mechanism of generating PVT1-NSMCE2 and CCDC26-NSMCE2. As PVT1 and CCDC26 are long intergenic non-coding RNAs (lincRNAs), our study suggests that the fusion genes involving lincRNAs potentially play as-yet-unknown oncogenic functional roles. Advancements in molecular cytogenetic techniques along with next generation sequencing will facilitate the understanding of tumorigenesis in hematological malignancies.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma, and is regarded as a heterogeneous group of lymphomas in terms of morphologic, immunologic, and cytogenetic features. The current standard therapy for DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy, which allows many patients to achieve disease cure. Despite recent progress in improving patient survival, 40% of DLBCL outcomes are still unsatisfactory. Gene expression profiling has been used to identify two distinct forms of DLBCL: the activated B-cell (ABC) subtype and the germinal center B-cell (GCB) subtype, which reflects normal B-cell differentiation. ABC DLBCL has been reported to show a more activated phenotype and a poorer prognosis than the GCB subtypes, with molecular diagnosis after R-CHOP therapy. Next generation sequencing identified unique oncogenic mechanisms and genetic complexity, which provided rational therapeutic targets. Recent studies suggest that patients with double-hit lymphoma, i.e., dual rearrangements of MYC and BCL2, have an extremely grim prognosis. Moreover, there are a number of biomarkers including CD5 and prognostic factors. Efforts to distinguish among these biomarkers will be crucial for devising individualized treatments in the future.

In 1832, Dr. Thomas Hodgkin reported the first cases with this malignancy, which came to be named Hodgkin's disease. The cells that are a hallmark of this disease, Hodgkin and Reed-Sternberg (HRS) cells, account for only 1% of those in tumor tissues, with the majority of cells in Hodgkin lymphoma being of various inflammatory types. Advances in molecular techniques have contributed to molecular biological analysis of HRS cells. Intriguingly, HRS cells are derived from germinal center B-cells, but have lost their B-cell gene-expression and co-express non-B-cell genes. Multiple signaling pathways, including the NFκB and JAK/STAT pathways, show deregulated activity in HRS cells, suggesting an important role for these pathways in the pathogenesis of Hodgkin lymphoma. This article describes the molecular pathological characteristics of HRS cells: 1) the cellular origin of HRS cells, 2) deregulated gene expression in HRS cells, 3) genetic alterations and 4) epigenetic alterations in HRS cells, 5) the lost B-cell phenotype of HRS cells, 6) the role of EBV in Hodgkin lymphoma pathogenesis, and 7) micro-environmental interactions between HRS and reactive cells.

Cumulative evidence suggests that at least some hematologic malignancies are derived from alterations of epigenetic machinery. Next generation sequencing has revealed recurrent mutations of genes related to DNA methylation and histone modification in myelodysplastic syndromes (MDS), acute myeloid leukemia, malignant lymphoma, and multiple myeloma. Both these pathways are targetable and specific inhibitors of their related proteins are currently in development. Among these novel therapies, hypomethylating agents have been approved for MDS, and recently, histone deacetylase inhibitors became available for T-cell lymphoma and multiple myeloma. Agents currently undergoing clinical trials include inhibitors of IDH2 targeting DNA methylation, and EZH2, Dot1L, and BRD4 inhibitors designed to target either writers or readers of post-translational modifications (PTMs) of histones. In a phase I setting, where the maximum tolerated dose has not been reached, efficacy was reported with these agents. Furthermore, Dot1bL and IDH2 inhibitors have been shown to induce differentiation of leukemic blasts in patients with MLL gene rearrangements and IDH2 mutations, respectively, thus providing functional evidence supporting the use of inhibitors of epigenetic mechanisms as a means of differentiation therapy for hematologic malignancies.

The ABL tyrosine kinase inhibitor (TKI) imatinib mesylate has dramatically changed the treatment of chronic myeloid leukemia (CML). However, resistance and intolerance have frequently been reported, particularly in patients with advanced-stage disease. There are several mechanisms underlying imatinib resistance. Notably, point mutations within the ABL kinase domain are the most critical cause of imatinib resistance. It has recently been recognized that adherence to ABL TKIs is very important for resistance. Four second-generation ATP competitive ABL TKIs, i.e., dasatinib, nilotinib, bosutinib and bafetinib, have been developed. The three TKIs other than bafetinib have been approved for CML in Japan. Although bosutinib has not been approved as a first line therapy, dasatinib and nilotinib demonstrated higher efficacy than imatinib for previously untreated CML in the chronic phase. Despite promising clinical results, the frequently observed mutant T315I is not effectively targeted by any of the second-generation ABL TKIs. Thus, a third-generation ABL TKI, ponatinib, was developed to inhibit all mutated BCR-ABL and showed clinical efficacy in CML cells harboring T315I. CML treatment is progressing rapidly and further advancements are highly anticipated. Moreover, it was recently reported that some portion of CML patients who achieved a sustained complete molecular response have been able to stop taking TKI agents.

Myeloproliferative neoplasms (MPNs) arise from hematopoietic stem cells (HSCs) with genetic abnormalities in combination with mutations in JAK2, MPL or CALR, which induce autosomal JAK-STAT pathway activation, and mutations in epigenetic regulator genes such as TET2 or DNMT3A. The prognosis of patients with polycythemia vera (PV) or essential thrombocythemia (ET) is relatively good, and the therapeutic goal in cases with PV or ET is to prevent thrombohemorrhagic complications. PV or ET patients at least 60 years of age or with a history of thrombosis are in a high-risk category, and are managed with low dose aspirin and cytoreductive therapy. Phlebotomy to maintain Ht<0.45 is also used to manage PV patients. The median survival for Japanese primary myelofibrosis (MF) patients is 3.9 years. Several factors including age>65 years, Hb<10 g/dl, the presence of constitutional symptoms, and the presence of blasts in blood were identified as being associated with shorter survival in MF patients. Those patients in the high-risk category are candidates for allogenic HSC transplantation (allo-HSCT), which is potentially curative but is also associated with higher therapy-related mortality. High-risk MF patients without indications for allo-HSCT are treated with JAK inhibitors, which can markedly ameliorate constitutional symptoms and splenomegaly, and might thereby lead to a degree of improvement in survival.

Familial predisposition to hematological malignancies has been recognized. Some of these malignancies are part of a well-characterized familial cancer predisposition syndrome, while others are independent of cancer predisposition, and demonstrate unique familial leukemia/lymphoma syndromes. Primary immunodeficiency is also strongly associated with the development of lymphoid malignancy. Primary immunodeficiency and leukemia/lymphoma are based on the same concept, which involves differentiation blockage. Bone marrow failure syndrome is also known to be associated with susceptibility to hematological malignancy development. Bone marrow failure syndrome exhibiting myeloid differentiation is also characterized as an aspect of primary immunodeficiency. Recent progress in genome wide association studies (GWAS) identified several single nucleotide polymorphisms (SNP) associated with leukemia/lymphoma development. Some of these genes were found to be functionally related to hematological malignancies. These discoveries are contributing to elucidation of the genetic background of leukemia/lymphoma development.

Currently, more than half of patients with acute myeloid leukemia (AML) are elderly. The prognosis is usually poor in these patients. Even among young people, there are still some cases with refractory or relapsed disease. Prognostic factors are categorized into leukemic, stage, and host factors. In elderly patients, the importance of host factors is increased relative to other factors. Cognitive and physical conditions should also be evaluated. Fitness for chemotherapy followed by hematopoietic cell transplantation is then determined. High-dose cytarabine or a purine nucleoside analogue combined chemotherapy is an option for treating relapsed or refractory cases. Gemtuzumab ozogamicin (GO) is not effective for single use. Results of clinical trials for GO combined chemotherapy were split. Doses and schedules still need to be discussed. Low dose chemotherapy has no survival benefit for elderly people. DNA hypomethylating agents have limited effects but do not achieve a cure. Novel drugs are under development. FLT3 inhibitors and/or IDH inhibitors are expected to exert beneficial effects. No therapy superior to conventional chemotherapy has yet been developed.