SCRUM-Japan was launched as a nation-wide genome screening consortium for recruiting patients to 35 sponsor-/investigator- initiated registration trials in collaboration with 15 pharmaceutical companies and 240 hospitals. During the first period between February 2015 and March 2017, a total of 4,805 patients have been enrolled. Genomic profiling of each cancer were analyzed and newdrug applications of label expansion are in preparation based on the results of several registration studies including investigator-initiated trial of vandetanib for RET fusion gene positive non-small cell lung cancer. In addition, on-time clinical-genome data sharing with industries and academic institutions and prospective cohort registry for new drug evaluation as a historical control data have already initiated, which will facilitate new agent development in Japan. In the second period started from April 2017, new studies using cutting-edge liquid biopsy and immune-genome panel for precision medi- cine will start soon. These efforts are attempted towards a leading group for innovative clinical/translations researches in the world.

Chromosomal rearrangements between 3q21 and 3q26 induce the abnormal expression of the EVI1 gene on 3q26, which results in leukemia and a poor prognosis. In the rearranged allele, we found that the GATA2 gene enhancer on 3q21 localizes in close proximity to the EVI1 gene. To examine the contribution of the GATA2 gene enhancer upon the abnormal expression of EVI1 and leukemogenesis, we established a leukemia mouse model (3q21q26 mouse) harboring a transgene recapitulating a 196-kb inverted allele between 3q21 and 3q26 by linking two bacterial artificial chromosome clones. The 3q21q26 mice demonstrated high EVI1 transgene expression specifically in hematopoietic progenitors and developed leukemia after 6 months of age. Of note, by deleting the GATA2 enhancer, EVI1 transgene expression and leukemogenesis were significantly suppressed, indicating that the GATA2 enhancer drives the abnormal expression of EVI1 in the rearranged allele and induces leukemogenesis. While the EVI1 gene gains the GATA2 enhancer, GATA2 gene loses its enhancer. Therefore, GATA2 expression levels are reduced in leukemic cells with such chromosomal rearrangements. To examine the contribution of GATA2 heterozygous deletion upon leukemogenesis, we crossed the 3q21q26 mice with Gata2 heterozygous knockout mice to generate compound mutant mice recapitulating both abnormal EVI1 expression and Gata2 heterozygous deletion. The compound mutant mice developed leukemia earlier than the 3q21q26 mice did. These results indicate that GATA2 heterozygous deletion accelerates leukemogenesis driven by the abnormal expression of EVI1.

Mononuclear phagocytes, such as monocytes and dendritic cells (DCs), are essential for tissue homeostasis and immunity. In adults, these cells develop from hematopoietic stem cells via a common progenitor population. We have been investigating the mechanism underlying the development of mononuclear phagocytes from the viewpoint of gene expression control by transcription factors. Particularly, IRF8, the loss of which causes immunodeficiency and chronic myeloid leukemia-like neutrophilia in mice and humans, promotes the development of monocytes and DCs, while it limits neutrophil differentiation. IRF8 cooperates with the myeloid master transcription factor, PU.1, in mononuclear phagocyte progenitors. KLF4 and BATF3 serve as critical transcription factors downstream of IRF8 to induce the differentiation of monocytes and DCs, respectively. Conversely, IRF8 blocks the activity of the transcription factor C/EBPα to suppress the neutrophil differentiation program. Indeed, Irf8-/- mononuclear phagocyte progenitors do not efficiently generate monocytes and DCs and, instead, aberrantly give rise to a large number of neutrophils. Our recent data have begun to uncover the vital role of IRF8 in the establishment of distal enhancers in mononuclear phagocyte progenitors. These results place IRF8 as a central regulator of the development of monocytes and DCs.

Chronic myeloid leukemia (CML) typically causes leukocytosis rather than thrombocytosis. We encountered two women in their thirties with remarkable thrombocytosis, whose platelet counts were over 3,000×103/µl, and without significant leukocytosis. Although their clinical findings resembled that of essential thrombocythemia (ET), they were diagnosed with CML because of the presence of Philadelphia chromosome. JAK2, CALR, and MPL were unmutated. On fluorescence in situ hybridization analysis, only 19.8% of granulocytes in case 2 were found to be BCR/ABL positive in peripheral blood (PB). We reviewed 11 CML cases whose platelet counts were over 2,000×103/µl, but their WBC counts were not significantly elevated (<12,000/µl). Most of them were young females with a normal or a high neutrophil alkaline phosphatase score and without immature myeloid cells in PB. These findings suggested that there is a subgroup of CML patients with marked thrombocytosis and without significant leukocytosis, which may be misdiagnosed as ET.

A 73-year-old woman presented a 3-year history of indolent enlargement of cutaneous tumor nodules. Peripheral blood flow cytometry revealed thrombocytopenia (platelets; 85,000/µl) and the presence of an abnormal, small B lymphocyte population (CD5+, CD10-, CD20+, CD22+, CD23dim, FMC7+, SmIgλ+, and SmIgκ-; 4,000/µl). Skin biopsy indicated infiltration of CD5+, CD10-, CD20+, BCL2+, BCL6+, and cyclin D1- atypical large B-cells, suggesting diffuse large B-cell lymphoma. Cytogenetic analysis of the peripheral blood revealed a complex karyotype [t (2;18) (p12;q21) and +12]. Fluorescence in situ hybridization detected the presence of BCL2 split signal and the absence of IGH/CCND1 fusion signal. Cervical lymph node biopsy indicated a pseudofollicular pattern. The sequence of immunoglobulin heavy chain variable region from the peripheral blood and the skin tumor contained the same mutated pattern, and therefore, confirmed clonality. Because the patient's clinical course and skin tumor were indolent, the possibility of Richter syndrome was discarded, and the final diagnosis was chronic lymphocytic leukemia/small lymphocytic lymphoma, Rai stage IV and Binet stage C. The patient achieved complete remission after 4 cycles of a fludarabine plus rituximab regimen, without disease progression since >1 year of treatment.

Soft tissue sarcoma(STS)is one of the rare and intractable cancers, and most types of STS are not sensitive to chemotherapy. Development of specific molecular target therapy for each type of STS is necessary. There are specific chromosome translocations in 20-30% of STS, but their products are mostly transcriptional factors, and target therapy for those factors are difficult to develop. Trabectedin is an alkylating agent and is also inhibit function of transcriptional factors, and shows efficacy for translocation-related sarcoma(TRS)such as myxoid liposarcoma. As molecular target therapies for gene mutations, success in molecular target therapy for c-kit and PDGFR mutation in GIST was followed by efficacy for rare sarcomas such as IMT or DFSP, but there are few developments in other sarcomas. STSs are frequently associated with angiogenesis and angiogenesis inhibitors such as pazopanib show some efficacy. Then immune checkpoint inhibitors also have been developed.

Diffuse large B-cell lymphoma (DLBCL), not otherwise specified, is the most common malignant lymphoma in the world. The recent progress of molecular techniques has proved its heterogeneity. Gene expression profiling for DLBCL, recently achieved using formalin-fixed paraffin-embedded samples, has identified two molecular subtypes, according to their cell of origin correlated with prognosis. Genomic abnormalities are roughly divided into translocations, amplifications/deletions, and mutations. Translocations involving MYC and BCL2 frequently co-occur in 5%-10% of DLBCL and are associated with aggressive clinical behavior with poor outcomes. Array CGH has identified some genetic alterations including deletions of tumor suppressor genes, such as CDKN2A, and amplifications of several genes involved in oncogenic pathway, such as NFκB. The next generation sequence identified numerous somatic gene mutations in DLBCL. Mutations of epigenome-associated genes, tumor suppressor genes, and NFκB-associated genes have been identified in cases of DLBCL. These mutations affect the function of gene products and play important roles in lymphomagenesis or the progression of DLBCL. This fact suggested that these mutations may affect clinicopathological findings, particularly prognosis. In this study, the most recent advances in genetic alterations and their association with clinicopathological findings of DLBCL were introduced and reviewed.

Epigenetic regulation holds a key role in gene expression due to its modulation of the structure and function of chromatin. Notably, epigenetic dysregulation is deeply involved in the pathogenesis of hematological malignancies. Polycomb group (PcG) genes encoding histone modifier proteins are representative epigenetic genes that regulate a variety of cellular functions, including self-renewal and multi-lineage differentiation of stem cells. Surprisingly, many PcG genes are targeted by deletions or somatic mutations or both in a number of hematological malignancies, such as myelodysplastic syndrome (MDS). PcG proteins form multiprotein complexes and exert either oncogenic or tumor-suppressive functions, depending on the tumor type. In MDS, they function as tumor suppressors. This review summarizes the current knowledge on deregulated polycomb function in the pathogenesis of MDS.

An 8-year-old Mongolian female was diagnosed with acute myeloid leukemia (AML) and treated at a hospital in Mongolia according to the BFM-AML2004 SR protocol. Although complete remission (CR) was achieved, chemotherapy was interrupted because of shortage of drugs. The patient moved to Japan 7 months after diagnosis. Screening for viral infection revealed the presence of hepatitis C virus (HCV) antibody and RNA. At 11 months after initial diagnosis, the patient experienced bone marrow relapse and a RUNX1-RUNX1T1 fusion transcript was detected. Considering the inadequate intensity of initial treatment and the persistent HCV infection, chemotherapy was preferred and initiated over hematopoietic cell transplantation. After the first course of induction therapy, a second CR was confirmed and the chimeric transcript disappeared. The viral load mildly increased during myelosuppression and transient elevation of liver enzymes was observed along with hematological recovery. HCV infection remained stable, without progression to reactivation of hepatitis C. Given the high risk of second relapse and liver fibrosis and sclerosis following chronic HCV infection, treatment against HCV may be indicated during second remission.

There have been dramatic recent advances in understanding the basic pathophysiology and treatment strategies for multiple myeloma (MM). Research has shown both a high inter-patient diversity and intra-clonal heterogeneity even in a single patient in terms of cytogenetic/molecular abnormalities, and has also identified marked diversity in the immunological factors involved in tumor surveillance among MM patients. In the presence of a variety of novel agents, including molecular-targeted agents, immunomodulatory agents, and monoclonal antibodies, the optimal translation of current knowledge on both molecular and immunologic findings into clinical use is crucial for managing MM. In addition, the application of the decision-making process for the selection of treatment strategies, the classification of disease risk, the prediction of outcome, and disease status monitoring have greatly influenced the clinical course of MM. In this review, we summarize recent advances in understanding the pathophysiology of MM, including molecular/cytogenetic/epigenetic abnormalities and immunologic dysregulation of both tumor and immune cells. In addition, we also briefly discuss the changes/innovations in both diagnostic approaches and treatment concepts.

Acute lymphoblastic leukemia (ALL) is seen in both children and adults, but its incidence peaks between 2 and 5 years and also increases in the older population. Although most children can be cured, the prognosis of adults with ALL remains poor. Recent identification of novel genetic alterations and sequence mutations has contributed to the elucidation of the pathogenesis of ALL. The World Health Organization classification was revised in 2016. ALL was included within the subgroup of myeloid neoplasms and acute leukemia. New provisional entities with recurrent abnormalities have been recognized and incorporated into the classification. Treatment of ALL involves some of the most complex chemotherapy combinations and treatment schedules used in oncology. Two main chemotherapy regimens are being used. The Berlin-Frankfurt-Münster framework consists of an induction regimen, consolidation regimen, reintensification regimen, and maintenance therapy and is mostly used in Europe for adult ALL trials. Another approach is to alternatively repeat two different intensive chemotherapy cycles, such as the hyper-CVAD regimen designed by investigators at the MD Anderson Cancer Center. Furthermore, the treatment of older patients with ALL is an unmet medical need. Novel targeted therapies, immunotherapies, and reduced-intensity SCT are promising approaches.

MicroRNAs(miRNAs)are small(18-25 nucleotides)noncoding RNA molecules that bind to partially complementary mRNA sequences, resulting in target degradation or translation inhibition. A single miRNA can influence the expression of hundreds of target genes, and miRNAs have been implicated as key molecules in various diseases, including cancer. Many studies have shown that the miRNAs play an important role in cancer cells and tumor microenvironment and may be biomarkers for early detection and therapeutic targets for various cancers. Recently, relationships between miRNAs and immunocheckpoint molecules have been focused on as new tumor progression associated mechanisms. As for biomarkers, cell-free miRNAs detected in body fluids(circulating miRNAs)have attached the attention of researchers due to their potential as tumor-specific and non-invasive biomarkers. In terms of strategies to use miRNAs as therapeutic targets, developments of tissue specific delivery systems, including lipid nanoparticles or exosome vectors, are progressing. Here we will review the mechanisms and clinical uses of miRNAs in cancer.

"Liquid biopsy"is a diagnostic medium to detect very small amount of tumor-derived molecules in blood for selecting precise clinical treatments and giving a diagnosis. This article focuses on circulating tumor DNA(ctDNA)and describes its features, clinical significance as well as future prospects with recent findings in this field. "Liquid biopsy"using ctDNAis facilitated by recent developments of highly sensitive technologies, including digital PCR. "BEAMing"is a digital PCR method that can detect rare mutations in ctDNAand will be introduced with some clinical evidences in this article. ctDNAis tumorderived fragmented DNAthat is circulating freely in the blood of a cancer patient. Tests for ctDNAare less invasive, easier than tissue-based tests to collect specimens and can be used repeatedly regardless of any cancer types. Emerging clinical evidences indicate that ctDNAtests show a high concordance rate with tissue-based tests in the identification of oncogene genotypes and can be used for real-time monitoring in vivo, such as prediction of clinical treatments, recurrence and drug resistance. "Liquid biopsy" using ctDNAcontinues to develop, but is promising to complement conventional tissue-based tests. Clinical applications of ctDNAtests are expected to expand as a useful diagnostic tools in areas of therapy selection and monitoring for drug resistance.

Cellular senescence is a state of irreversible cell proliferation arrest provoked by a persistent DNA damage induced by a variety of potentially oncogenic signals, and it functions as a primary tumor-suppression mechanism. Recent studies, however, revealed that senescent cells have the potential to secrete numerous inflammatory cytokines, chemokines, growth factors and matrix-remodeling factors, since unlike apoptotic cells, senescent cells are viable for a long period of time. This newly identified phenotype of cellular senescence, called senescence-associated secretory phenotype(SASP or senescence-associated secretome), could potentially provide beneficial effects, such as tissue repair, but sometimes could induce deleterious side effects, such as cancer progression, depending on the biological context.