Details of a Researcher - Kataoka, Keisuke

Papers - Kataoka, Keisuke

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PD-L1 expression on tumor or stromal cells of nodal cytotoxic T-cell lymphoma: A clinicopathological study of 50 cases

Yamashita, D., Shimada, K., Kohno, K., Kogure, Y., Kataoka, K., Takahara, T., Suzuki, Y., Satou, A., Sakakibara, A., Nakamura, S., Asano, N. and Kato, S.

Pathol Int 2020.05

ISSN 1440-1827

Inhibitors of programmed cell-death 1 (PD-1) and programmed cell-death ligand 1 (PD-L1) have revolutionized cancer therapy. Nodal cytotoxic T-cell lymphoma (CTL) is characterized by a poorer prognosis compared to nodal non-CTLs. Here we investigated PD-L1 expression in 50 nodal CTL patients, with and without EBV association (25 of each). We identified seven patients (14%) with neoplastic PD-L1 (nPD-L1) expression on tumor cells, including three males and four females, with a median age of 66 years. One of the seven cases was TCRalphabeta type, three were TCRgammadelta type and three were TCR-silent type. Six of the seven cases exhibited a lethal clinical course despite multi-agent chemotherapy, of whom four patients died within one year of diagnosis. Morphological findings were uniform, with six cases showing centroblastoid appearance. Among nPD-L1(+) cases, two of three examined had structural variations of PD-L1 disrupting 3'-UTR region. Notably, all of the TCRgammadelta-type nodal CTL cases showed nPD-L1 or miPD-L1 positivity (3 and 10 cases, respectively). TCRgammadelta-type cases comprised 42% of nPD-L1(+) cases (P = 0.043 vs. PD-L1(-) ), and 35% of miPD-L1(+) cases (P = 0.037 vs. PD-L1(-) ). The results indicate that PD-L1(+) nodal CTL cases, especially of the TCRgammadelta type, are potential candidates for anti-PD-1/PD-L1 therapies.

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LUBAC accelerates B-cell lymphomagenesis by conferring B cells resistance to genotoxic stress

Jo, T., Nishikori, M., Kogure, Y., Arima, H., Sasaki, K., Sasaki, Y., Nakagawa, T., Iwai, F., Momose, S., Shiraishi, A., Kiyonari, H., Kagaya, N., Onuki, T., Shin-Ya, K., Yoshida, M., Kataoka, K., Ogawa, S., Iwai, K. and Takaori-Kondo, A.

Blood 2020.04

ISSN 1528-0020

Linear ubiquitin chain assembly complex (LUBAC) is a key regulator of NF-kB signaling. Activating single-nucleotide polymorphisms of HOIP, the catalytic subunit of LUBAC, are enriched in patients with activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL), and expression of HOIP which parallels LUBAC activity is elevated in ABC-DLBCL samples. Thus, to clarify the precise roles of LUBAC in lymphomagenesis, we generated a mouse model with augmented expression of HOIP in B cells. Interestingly, augmented HOIP expression facilitated DLBCL-like B-cell lymphomagenesis driven by MYD88-activating mutation. The developed lymphoma cells partly shared somatic gene mutations with human DLBCLs, with increased frequency of a typical AID mutation pattern. In vitro analysis revealed that HOIP overexpression protected B cells from DNA damage-induced cell death through NF-kB activation, and the analysis of human DLBCL database showed that expression of HOIP positively correlated with gene signatures representing regulation of apoptosis signaling, as well as NF-kB signaling. These results indicate that HOIP facilitates lymphomagenesis by preventing cell death and augmenting NF-kB signaling, leading to accumulation of AID-mediated mutations. Furthermore, a natural compound that specifically inhibits LUBAC was shown to suppress the tumor growth in a mouse transplantation model. Collectively, our data indicates that LUBAC is crucially involved in B-cell lymphomagenesis through protection against DNA damage-induced cell death, and is a suitable therapeutic target for B-cell lymphomas.

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Combined Cohesin-RUNX1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes

Ochi, Y., Kon, A., Sakata, T., Nakagawa, M. M., Nakazawa, N., Kakuta, M., Kataoka, K., Koseki, H., Nakayama, M., Morishita, D., Tsuruyama, T., Saiki, R., Yoda, A., Okuda, R., Yoshizato, T., Yoshida, K., Shiozawa, Y., Nannya, Y., Kotani, S., Kogure, Y., Kakiuchi, N., Nishimura, T., Makishima, H., Malcovati, L., Yokoyama, A., Takeuchi, K., Sugihara, E., Sato, T. A., Sanada, M., Takaori-Kondo, A., Cazzola, M., Kengaku, M., Miyano, S., Shirahige, K., Suzuki, H. I. and Ogawa, S.

Cancer Discov 2020.04

ISSN 2159-8290

STAG2 encodes a cohesin component and is frequently mutated in myeloid neoplasms, showing highly significant comutation patterns with other drivers, including RUNX1. However, the molecular basis of cohesin-mutated leukemogenesis remains poorly understood. Here we show a critical role of an interplay between STAG2 and RUNX1 in the regulation of enhancer-promoter looping and transcription in hematopoiesis. Combined loss of STAG2 and RUNX1, which colocalize at enhancer-rich, CTCF-deficient sites, synergistically attenuates enhancer-promoter loops, particularly at sites enriched for RNA polymerase II and Mediator, and deregulates gene expression, leading to myeloid-skewed expansion of hematopoietic stem/progenitor cells (HSPC) and myelodysplastic syndromes (MDS) in mice. Attenuated enhancer-promoter loops in STAG2/RUNX1-deficient cells are associated with downregulation of genes with high basal transcriptional pausing, which are important for regulation of HSPCs. Downregulation of high-pausing genes is also confirmed in STAG2-cohesin-mutated primary leukemia samples. Our results highlight a unique STAG2-RUNX1 interplay in gene regulation and provide insights into cohesin-mutated leukemogenesis. SIGNIFICANCE: We demonstrate a critical role of an interplay between STAG2 and a master transcription factor of hematopoiesis, RUNX1, in MDS development, and further reveal their contribution to regulation of high-order chromatin structures, particularly enhancer-promoter looping, and the link between transcriptional pausing and selective gene dysregulation caused by cohesin deficiency.

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TET2 haploinsufficiency alters reprogramming into induced pluripotent stem cells

Secardin, L., Limia, C. E. G., di Stefano, A., Bonamino, M. H., Saliba, J., Kataoka, K., Rehen, S. K., Raslova, H., Marty, C., Ogawa, S., Vainchenker, W., Monte-Mor, Bdcr and Plo, I.

Stem Cell Res 44 101755 2020.03

ISSN 1876-7753

The discovery of the Ten-Eleven Translocation (TET) protein family was initiated by the identification of the MLL partner TET1, and of mutations in the TET2 gene in hematological malignancies including myeloproliferative neoplasms (MPN). TET1, 2 and 3 proteins hydroxylate 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC) and further oxidize 5-hmC into 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC). Previous studies highlight the involvement of TET proteins in somatic cells reprogramming into induced pluripotent stem cells (iPSC), particularly Tet1 and 2 in mouse and TET1 in human. Here, we asked whether endogenous TET2 knockdown also displays this function. Using different shRNA against TET2, we provide evidence that TET2 strongly decreases the reprogramming of human hematopoietic progenitor cells into iPSC. Importantly, using 2 MPN patients, we observed that TET2 mutations affecting catalytic domain allowed iPSC generation. Instead, using another TET2 and TET3-mutated patient, we could only reprogram IPSC with TET3 mutation alone, suggesting that the type of TET2 mutation and/or the cooperation with TET3 mutations may alter the reprogramming activity. Altogether, this work highlights the importance of endogenous TET in the reprogramming process of human hematopoietic progenitors.

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Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non-small cell lung cancer

Sugiyama, E., Togashi, Y., Takeuchi, Y., Shinya, S., Tada, Y., Kataoka, K., Tane, K., Sato, E., Ishii, G., Goto, K., Shintani, Y., Okumura, M., Tsuboi, M. and Nishikawa, H.

Sci Immunol 5 ( 43 ) 2020.01

ISSN 2470-9468

The clinical efficacy of anti-PD-1 (programmed cell death-1) monoclonal antibody (mAb) against cancers with oncogenic driver gene mutations, which often harbor a low tumor mutation burden, is variable, suggesting different contributions of each driver mutation to immune responses. Here, we investigated the immunological phenotypes in the tumor microenvironment (TME) of epidermal growth factor receptor (EGFR)-mutated lung adenocarcinomas, for which anti-PD-1 mAb is largely ineffective. Whereas EGFR-mutated lung adenocarcinomas had a noninflamed TME, CD4(+) effector regulatory T cells, which are generally present in the inflamed TME, showed high infiltration. The EGFR signal activated cJun/cJun N-terminal kinase and reduced interferon regulatory factor-1; the former increased CCL22, which recruits CD4(+) regulatory T cells, and the latter decreased CXCL10 and CCL5, which induce CD8(+) T cell infiltration. The EGFR inhibitor erlotinib decreased CD4(+) effector regulatory T cells infiltration in the TME and in combination with anti-PD-1 mAb showed better antitumor effects than either treatment alone. Our results suggest that EGFR inhibitors when used in conjunction with anti-PD-1 mAb could increase the efficacy of immunotherapy in lung adenocarcinomas.

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TP53 and PTEN mutations were shared in concurrent germ cell tumor and acute megakaryoblastic leukemia

Akizuki, K., Sekine, M., Kogure, Y., Kameda, T., Shide, K., Koya, J., Kamiunten, A., Kubuki, Y., Tahira, Y., Hidaka, T., Kiwaki, T., Tanaka, H., Sato, Y., Kataoka, H., Kataoka, K. and Shimoda, K.

BMC Cancer 20 ( 1 ) 5 2020.01

ISSN 1471-2407

BACKGROUND: The occurrence of a mediastinal germ cell tumor (GCT) and hematological malignancy in the same patient is very rare. Due to its rarity, there have been only two reports of the concurrent cases undergoing detailed genetic analysis with whole-exome sequencing (WES), and the possible clonal relationship between the both tumors remained not fully elucidated. METHODS: We performed whole-exome sequencing analysis of mediastinal GCT and acute myeloid leukemia (AML) samples obtained from one young Japanese male adult patient with concurrent both tumors, and investigated the possible clonal relationship between them. RESULTS: Sixteen somatic mutations were detected in the mediastinal GCT sample and 18 somatic mutations in the AML sample. Mutations in nine genes, including TP53 and PTEN both known as tumor suppressor genes, were shared in both tumors. CONCLUSIONS: All in our case and in the previous two cases with concurrent mediastinal GCT and AML undergoing with whole-exome sequencing analysis, TP53 and PTEN mutations were commonly shared in both tumors. These data not only suggest that these tumors share a common founding clone, but also indicate that associated mediastinal GCT and AML harboring TP53 and PTEN mutations represent a unique biological entity.

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Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis

Kakiuchi, N., Yoshida, K., Uchino, M., Kihara, T., Akaki, K., Inoue, Y., Kawada, K., Nagayama, S., Yokoyama, A., Yamamoto, S., Matsuura, M., Horimatsu, T., Hirano, T., Goto, N., Takeuchi, Y., Ochi, Y., Shiozawa, Y., Kogure, Y., Watatani, Y., Fujii, Y., Kim, S. K., Kon, A., Kataoka, K., Yoshizato, T., Nakagawa, M. M., Yoda, A., Nanya, Y., Makishima, H., Shiraishi, Y., Chiba, K., Tanaka, H., Sanada, M., Sugihara, E., Sato, T. A., Maruyama, T., Miyoshi, H., Taketo, M. M., Oishi, J., Inagaki, R., Ueda, Y., Okamoto, S., Okajima, H., Sakai, Y., Sakurai, T., Haga, H., Hirota, S., Ikeuchi, H., Nakase, H., Marusawa, H., Chiba, T., Takeuchi, O., Miyano, S., Seno, H. and Ogawa, S.

Nature 577 ( 7789 ) 260 - 265 2020.01

ISSN 1476-4687

Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer(1-3). However, how such cycles affect the clonal composition of tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.

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Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling

Watatani, Y., Sato, Y., Miyoshi, H., Sakamoto, K., Nishida, K., Gion, Y., Nagata, Y., Shiraishi, Y., Chiba, K., Tanaka, H., Zhao, L., Ochi, Y., Takeuchi, Y., Takeda, J., Ueno, H., Kogure, Y., Shiozawa, Y., Kakiuchi, N., Yoshizato, T., Nakagawa, M. M., Nanya, Y., Yoshida, K., Makishima, H., Sanada, M., Sakata-Yanagimoto, M., Chiba, S., Matsuoka, R., Noguchi, M., Hiramoto, N., Ishikawa, T., Kitagawa, J., Nakamura, N., Tsurumi, H., Miyazaki, T., Kito, Y., Miyano, S., Shimoda, K., Takeuchi, K., Ohshima, K., Yoshino, T., Ogawa, S. and Kataoka, K.

Leukemia 33 ( 12 ) 2867 - 2883 2019.12

ISSN 1476-5551

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a diagnosis of exclusion, being the most common entity in mature T-cell neoplasms, and its molecular pathogenesis remains significantly understudied. Here, combining whole-exome and targeted-capture sequencing, gene-expression profiling, and immunohistochemical analysis of tumor samples from 133 cases, we have delineated the entire landscape of somatic alterations, and discovered frequently affected driver pathways in PTCL, NOS, with and without a T-follicular helper (TFH) cell phenotype. In addition to previously reported mutational targets, we identified a number of novel recurrently altered genes, such as KMT2C, SETD1B, YTHDF2, and PDCD1. We integrated these genetic drivers using hierarchical clustering and identified a previously undescribed molecular subtype characterized by TP53 and/or CDKN2A mutations and deletions in non-TFH PTCL, NOS. This subtype exhibited different prognosis and unique genetic features associated with extensive chromosomal instability, which preferentially affected molecules involved in immune escape and transcriptional regulation, such as HLA-A/B and IKZF2. Taken together, our findings provide novel insights into the molecular pathogenesis of PTCL, NOS by highlighting their genetic heterogeneity. These results should help to devise a novel molecular classification of PTCLs and to exploit a new therapeutic strategy for this group of aggressive malignancies.

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Integrated genetic and epigenetic analysis revealed heterogeneity of acute lymphoblastic leukemia in Down syndrome

Kubota, Y., Uryu, K., Ito, T., Seki, M., Kawai, T., Isobe, T., Kumagai, T., Toki, T., Yoshida, K., Suzuki, H., Kataoka, K., Shiraishi, Y., Chiba, K., Tanaka, H., Ohki, K., Kiyokawa, N., Kagawa, J., Miyano, S., Oka, A., Hayashi, Y., Ogawa, S., Terui, K., Sato, A., Hata, K., Ito, E. and Takita, J.

Cancer Sci 110 ( 10 ) 3358 - 3367 2019.10

ISSN 1349-7006

Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (ALL). Compared to children with ALL and no DS (non-DS-ALL), those with DS and ALL (DS-ALL) harbor uncommon genetic alterations, suggesting DS-ALL could have distinct biological features. Recent studies have implicated several genes on chromosome 21 in DS-ALL, but the precise mechanisms predisposing children with DS to ALL remain unknown. Our integrated genetic/epigenetic analysis revealed that DS-ALL was highly heterogeneous with many subtypes. Although each subtype had genetic/epigenetic profiles similar to those found in non-DS-ALL, the subtype distribution differed significantly between groups. The Philadelphia chromosome-like subtype, a high-risk B-cell lineage variant relatively rare among the entire pediatric ALL population, was the most common form in DS-ALL. Hypermethylation of RUNX1 on chromosome 21 was also found in DS-ALL, but not non-DS-ALL. RUNX1 is essential for differentiation of blood cells, especially B cells; thus, hypermethylation of the RUNX1 promoter in B-cell precursors might be associated with increased incidence of B-cell precursor ALL in DS patients.

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PAK Kinase Inhibition Has Therapeutic Activity in Novel Preclinical Models of Adult T-Cell Leukemia/Lymphoma

Chung, E. Y., Mai, Y., Shah, U. A., Wei, Y., Ishida, E., Kataoka, K., Ren, X., Pradhan, K., Bartholdy, B., Wei, X., Zou, Y., Zhang, J., Ogawa, S., Steidl, U., Zang, X., Verma, A., Janakiram, M. and Ye, B. H.

Clin Cancer Res 25 ( 12 ) 3589 - 3601 2019.06

ISSN 1078-0432

PURPOSE: To evaluate therapeutic activity of PAK inhibition in ATLL and to characterize the role of PAK isoforms in cell proliferation, survival, and adhesion of ATLL cells in preclinical models. EXPERIMENTAL DESIGN: Frequency and prognostic impact of PAK2 amplification were evaluated in an ATLL cohort of 370 cases. Novel long-term cultures and in vivo xenograft models were developed using primary ATLL cells from North American patients. Two PAK inhibitors were used to block PAK kinase activity pharmacologically. siRNA-based gene silencing approach was used to genetically knockdown (KD) PAK1 and PAK2 in ATLL cell lines. RESULTS: PAK1/2/4 are the three most abundantly expressed PAK family members in ATLL. PAK2 amplifications are seen in 24% of ATLLs and are associated with worse prognosis in a large patient cohort. The pan-PAK inhibitor PF-3758309 (PF) has strong in vitro and in vivo activity in a variety of ATLL preclinical models. These activities of PF are likely attributed to its ability to target several PAK isoforms simultaneously because genetic silencing of either PAK1 or PAK2 produced more modest effects. PAK2 plays a major role in CADM1-mediated stromal interaction, which is an important step in systemic dissemination of the disease. This finding is consistent with the observation that PAK2 amplification is more frequent in aggressive ATLLs and correlates with inferior outcome. CONCLUSIONS: PAK2, a gene frequently amplified in ATLL, facilitates CADM1-mediated stromal interaction and promotes survival of ATLL cells. Taken together, PAK inhibition may hold significant promise as a targeted therapy for aggressive ATLLs.

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Decreased RORC expression and downstream signaling in HTLV-1-associated adult T-cell lymphoma/leukemia uncovers an antiproliferative IL17 link: A potential target for immunotherapy?

Subramanian, K., Dierckx, T., Khouri, R., Menezes, S. M., Kagdi, H., Taylor, G. P., Farre, L., Bittencourt, A., Kataoka, K., Ogawa, S. and Van Weyenbergh, J.

Int J Cancer 144 ( 7 ) 1664 - 1675 2019.04

ISSN 1097-0215

Retinoic acid-related drugs have shown promising pre-clinical activity in Adult T-cell Leukemia/Lymphoma, but RORC signaling has not been explored. Therefore, we investigated transcriptome-wide interactions of the RORC pathway in HTLV-1 and ATL, using our own and publicly available gene expression data for ATL and other leukemias. Gene expression data from ATL patients were analyzed using WGCNA to determine gene modules and their correlation to clinical and molecular data. Both PBMCs and CD4(+) T-Cells exhibited decreased RORC expression in four different ATL cohorts. A small subset of RORC(hi) ATL patients was identified with significantly lower pathognomonic CADM1 and HBZ levels but similar levels of other ATL markers (CD4/CD25/CCR4), hinting at a less aggressive ATL subtype. An age-dependent decrease in RORC expression was found in HTLV-1-infected individuals, but not in healthy controls, suggesting an early molecular event predisposing to leukemogenesis. Genes upstream of RORC signaling were members of a proliferative gene module (containing proliferation markers PCNA/Ki67), whereas downstream members clustered in an anti-proliferative gene module. IL17C transcripts showed the strongest negative correlation to PCNA in both ATL cohorts, which was replicated in two large cohorts of T- and B-cell acute lymphoid leukemia (ALL). Finally, IL17C expression in purified CD4 + CCR4 + CD26-CD7- "ATL-like" cells from HTLV-1-infected individuals and ATL patients was negatively correlated with clonality, underscoring a possible antileukemic/antiproliferative role. In conclusion, decreased RORC expression and downstream signaling might represent an early event in ATL pathogenesis. An antiproliferative IL17C/PCNA link is shared between ATL, T-ALL and B-ALL, suggesting (immuno)therapeutic benefit of boosting RORC/IL17 signaling.

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Identification of enhancer of mRNA decapping 4 as a novel fusion partner of MLL in acute myeloid leukemia

Becker, H., Greve, G., Kataoka, K., Mallm, J. P., Duque-Afonso, J., Ma, T., Niemoller, C., Pantic, M., Duyster, J., Cleary, M. L., Schuler, J., Rippe, K., Ogawa, S. and Lubbert, M.

Blood Adv 3 ( 5 ) 761 - 765 2019.03

ISSN 2473-9537

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Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas

Kataoka, K., Miyoshi, H., Sakata, S., Dobashi, A., Couronne, L., Kogure, Y., Sato, Y., Nishida, K., Gion, Y., Shiraishi, Y., Tanaka, H., Chiba, K., Watatani, Y., Kakiuchi, N., Shiozawa, Y., Yoshizato, T., Yoshida, K., Makishima, H., Sanada, M., Onozawa, M., Teshima, T., Yoshiki, Y., Ishida, T., Suzuki, K., Shimada, K., Tomita, A., Kato, M., Ota, Y., Izutsu, K., Demachi-Okamura, A., Akatsuka, Y., Miyano, S., Yoshino, T., Gaulard, P., Hermine, O., Takeuchi, K., Ohshima, K. and Ogawa, S.

Leukemia 2019.01

ISSN 1476-5551

Viral infection induces potent cellular immunity and activated intracellular signaling, which may dictate the driver events involved in immune escape and clonal selection of virus-associated cancers, including Epstein-Barr virus (EBV)-positive lymphomas. Here, we thoroughly interrogated PD-L1/PD-L2-involving somatic aberrations in 384 samples from various lymphoma subtypes using high-throughput sequencing, particularly focusing on virus-associated lymphomas. A high frequency of PD-L1/PD-L2-involving genetic aberrations was observed in EBV-positive lymphomas [33 (22%) of 148 cases], including extranodal NK/T-cell lymphoma (ENKTL, 23%), aggressive NK-cell leukemia (57%), systemic EBV-positive T-cell lymphoproliferative disorder (17%) as well as EBV-positive diffuse large B-cell lymphoma (DLBCL, 19%) and peripheral T-cell lymphoma-not otherwise specified (15%). Predominantly causing a truncation of the 3'-untranslated region, these alterations represented the most prevalent somatic lesions in ENKTL. By contrast, the frequency was much lower in EBV-negative lymphomas regardless of histology type [12 (5%) of 236 cases]. Besides PD-L1/PD-L2 alterations, EBV-positive DLBCL exhibited a genetic profile distinct from EBV-negative one, characterized by frequent TET2 and DNMT3A mutations and the paucity of CD79B, MYD88, CDKN2A, and FAS alterations. Our findings illustrate unique genetic features of EBV-associated lymphomas, also suggesting a potential role of detecting PD-L1/PD-L2-involving lesions for these lymphomas to be effectively targeted by immune checkpoint blockade.

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Yokoyama, A., Kakiuchi, N., Yoshizato, T., Nannya, Y., Suzuki, H., Takeuchi, Y., Shiozawa, Y., Sato, Y., Aoki, K., Kim, S. K., Fujii, Y., Yoshida, K., Kataoka, K., Nakagawa, M. M., Inoue, Y., Hirano, T., Shiraishi, Y., Chiba, K., Tanaka, H., Sanada, M., Nishikawa, Y., Amanuma, Y., Ohashi, S., Aoyama, I., Horimatsu, T., Miyamoto, S., Tsunoda, S., Sakai, Y., Narahara, M., Brown, J. B., Sato, Y., Sawada, G., Mimori, K., Minamiguchi, S., Haga, H., Seno, H., Miyano, S., Makishima, H., Muto, M. and Ogawa, S.

Nature 565 ( 7739 ) 312 - 317 2019.01

ISSN 1476-4687

Clonal expansion in aged normal tissues has been implicated in the development of cancer. However, the chronology and risk dependence of the expansion are poorly understood. Here we intensively sequence 682 micro-scale oesophageal samples and show, in physiologically normal oesophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with ageing, and ultimately replace almost the entire oesophageal epithelium in the extremely elderly. Compared with mutations in oesophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal oesophageal epithelia; these mutations can be acquired before late adolescence (as early as early infancy) and significantly increase in number with heavy smoking and drinking. The remodelling of the oesophageal epithelium by driver-mutated clones is an inevitable consequence of normal ageing, which-depending on lifestyle risks-may affect cancer development.

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More accurate prognostic prediction in diffuse large B-cell lymphoma: beyond cell-of-origin

Koya, J. and Kataoka, K.

Ann Oncol 29 ( 12 ) 2284 - 2286 2018.12

ISSN 1569-8041

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Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate

Taoka, K., Arai, S., Kataoka, K., Hosoi, M., Miyauchi, M., Yamazaki, S., Honda, A., Aixinjueluo, W., Kobayashi, T., Kumano, K., Yoshimi, A., Otsu, M., Niwa, A., Nakahata, T., Nakauchi, H. and Kurokawa, M.

Sci Rep 8 ( 1 ) 15855 2018.10

ISSN 2045-2322

Chronic myelomonocytic leukemia (CMML) is an entity of myelodysplastic syndrome/myeloproliferative neoplasm. Although CMML can be cured with allogeneic stem cell transplantation, its prognosis is generally very poor due to the limited efficacy of chemotherapy and to the patient's age, which is usually not eligible for transplantation. Comprehensive analysis of CMML pathophysiology and the development of therapeutic agents have been limited partly due to the lack of cell lines in CMML and the limited developments of mouse models. After successfully establishing patient's derived disease-specific induced pluripotent stem cells (iPSCs) derived from a patient with CMML, we utilized these CMML-iPSCs to achieve hematopoietic re-differentiation in vitro, created a humanized CMML mouse model via teratomas, and developed a drug-testing system. The clinical characteristics of CMML were recapitulated following hematopoietic re-differentiation in vitro and a humanized CMML mouse model in vivo. The drug-testing system using CMML-iPSCs identified a MEK inhibitor, a Ras inhibitor, and liposomal clodronate as potential drugs for treating CMML. Clodronate is a drug commonly used as a bisphosphonate for osteoporosis. In this study, the liposomalization of clodronate enhanced its effectiveness in these assays, suggesting that this variation of clodronate may be adopted as a repositioned drug for CMML therapy.

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North American ATLL has a distinct mutational and transcriptional profile and responds to epigenetic therapies

Shah, U. A., Chung, E. Y., Giricz, O., Pradhan, K., Kataoka, K., Gordon-Mitchell, S., Bhagat, T. D., Mai, Y., Wei, Y., Ishida, E., Choudhary, G. S., Joseph, A., Rice, R., Gitego, N., Parrish, C., Bartenstein, M., Goel, S., Mantzaris, I., Shastri, A., Derman, O., Binder, A., Gritsman, K., Kornblum, N., Braunschweig, I., Bhagat, C., Hall, J., Graber, A., Ratner, L., Wang, Y., Ogawa, S., Verma, A., Ye, B. H. and Janakiram, M.

Blood 132 ( 14 ) 1507 - 1518 2018.10

ISSN 1528-0020

Adult T-cell leukemia lymphoma (ATLL) is a rare T cell neoplasm that is endemic in Japanese, Caribbean, and Latin American populations. Most North American ATLL patients are of Caribbean descent and are characterized by high rates of chemo-refractory disease and worse prognosis compared with Japanese ATLL. To determine genomic differences between these 2 cohorts, we performed targeted exon sequencing on 30 North American ATLL patients and compared the results with the Japanese ATLL cases. Although the frequency of TP53 mutations was comparable, the mutation frequency in epigenetic and histone modifying genes (57%) was significantly higher, whereas the mutation frequency in JAK/STAT and T-cell receptor/NF-kappaB pathway genes was significantly lower. The most common type of epigenetic mutation is that affecting EP300 (20%). As a category, epigenetic mutations were associated with adverse prognosis. Dissimilarities with the Japanese cases were also revealed by RNA sequencing analysis of 9 primary patient samples. ATLL samples with a mutated EP300 gene have decreased total and acetyl p53 protein and a transcriptional signature reminiscent of p53-mutated cancers. Most importantly, decitabine has highly selective single-agent activity in the EP300-mutated ATLL samples, suggesting that decitabine treatment induces a synthetic lethal phenotype in EP300-mutated ATLL cells. In conclusion, we demonstrate that North American ATLL has a distinct genomic landscape that is characterized by frequent epigenetic mutations that are targetable preclinically with DNA methyltransferase inhibitors.

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Molecular pathogenesis of disease progression in MLL-rearranged AML

Kotani, S., Yoda, A., Kon, A., Kataoka, K., Ochi, Y., Shiozawa, Y., Hirsch, C., Takeda, J., Ueno, H., Yoshizato, T., Yoshida, K., Nakagawa, M. M., Nannya, Y., Kakiuchi, N., Yamauchi, T., Aoki, K., Shiraishi, Y., Miyano, S., Maeda, T., Maciejewski, J. P., Takaori-Kondo, A., Ogawa, S. and Makishima, H.

Leukemia 2018.09

ISSN 1476-5551

Leukemic relapse is frequently accompanied by progressively aggressive clinical course. To understand the molecular mechanism of leukemic relapse, MLL/AF9-transformed mouse leukemia cells were serially transplanted in C57BL/6 mice (N = 96) by mimicking repeated recurrences, where mutations were monitored by exome sequencing (N = 42). The onset of leukemia was progressively promoted with advanced transplants, during which increasing numbers of somatic mutations were acquired (P < 0.005). Among these, mutations in Ptpn11 (p.G60R) and Braf (p.V637E) corresponded to those identified in human MLL-AML, while recurrent mutations affecting Msn (p.R295C) were observed only in mouse but not in human MLL-AML. Another mutated gene of interest was Gnb2 which was reported to be recurrently mutated in various hematological neoplasms. Gnb2 mutations (p.G77R) were significantly increased in clone size (P = 0.007) and associated with earlier leukemia onset (P = 0.011). GNB2 transcripts were significantly upregulated in human MLL-AML compared to MLL-negative AML (P < 0.05), which was supported by significantly increased Gnb2 transcript induced by MLL/AF9 overexpression (P < 0.001). In in vivo model, both mutation and overexpression of GNB2 caused leukemogenesis, and downregulation of GNB2 expression reduced proliferative potential and survival benefit, suggesting a driver role of GNB2. In conclusion, alterations of driver genes over time may play an important role in the progression of MLL-AML.

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Aberrant splicing and defective mRNA production induced by somatic spliceosome mutations in myelodysplasia

Shiozawa, Y., Malcovati, L., Galli, A., Sato-Otsubo, A., Kataoka, K., Sato, Y., Watatani, Y., Suzuki, H., Yoshizato, T., Yoshida, K., Sanada, M., Makishima, H., Shiraishi, Y., Chiba, K., Hellstrom-Lindberg, E., Miyano, S., Ogawa, S. and Cazzola, M.

Nat Commun 9 ( 1 ) 3649 2018.09

ISSN 2041-1723

Spliceosome mutations are frequently found in myelodysplasia. Splicing alterations induced by these mutations, their precise targets, and the effect at the transcript level have not been fully elucidated. Here we report transcriptomic analyses of 265 bone marrow samples from myelodysplasia patients, followed by a validation using CRISPR/Cas9-mediated gene editing and an assessment of nonsense-mediated decay susceptibility. Small but widespread reduction of intron-retaining isoforms is the most frequent splicing alteration in SF3B1-mutated samples. SF3B1 mutation is also associated with 3' splice site alterations, leading to the most pronounced reduction of canonical transcripts. Target genes include tumor suppressors and genes of mitochondrial iron metabolism or heme biosynthesis. Alternative exon usage is predominant in SRSF2- and U2AF1-mutated samples. Usage of an EZH2 cryptic exon harboring a premature termination codon is increased in both SRSF2- and U2AF1-mutated samples. Our study reveals a landscape of splicing alterations and precise targets of various spliceosome mutations.

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De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome

Toki, T., Yoshida, K., Wang, R., Nakamura, S., Maekawa, T., Goi, K., Katoh, M. C., Mizuno, S., Sugiyama, F., Kanezaki, R., Uechi, T., Nakajima, Y., Sato, Y., Okuno, Y., Sato-Otsubo, A., Shiozawa, Y., Kataoka, K., Shiraishi, Y., Sanada, M., Chiba, K., Tanaka, H., Terui, K., Sato, T., Kamio, T., Sakaguchi, H., Ohga, S., Kuramitsu, M., Hamaguchi, I., Ohara, A., Kanno, H., Miyano, S., Kojima, S., Ishiguro, A., Sugita, K., Kenmochi, N., Takahashi, S., Eto, K., Ogawa, S. and Ito, E.

Am J Hum Genet 103 ( 3 ) 440 - 447 2018.09

ISSN 1537-6605

Inherited bone-marrow-failure syndromes (IBMFSs) include heterogeneous genetic disorders characterized by bone-marrow failure, congenital anomalies, and an increased risk of malignancy. Many lines of evidence have suggested that p53 activation might be central to the pathogenesis of IBMFSs, including Diamond-Blackfan anemia (DBA) and dyskeratosis congenita (DC). However, the exact role of p53 activation in each clinical feature remains unknown. Here, we report unique de novo TP53 germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC. TP53 is a tumor-suppressor gene most frequently mutated in human cancers, and occasional germline variants occur in Li-Fraumeni cancer-predisposition syndrome. Most of these mutations affect the core DNA-binding domain, leading to compromised transcriptional activities. In contrast, the variants found in the two individuals studied here caused the same truncation of the protein, resulting in the loss of 32 residues from the C-terminal domain (CTD). Unexpectedly, the p53 mutant had augmented transcriptional activities, an observation not previously described in humans. When we expressed this mutant in zebrafish and human-induced pluripotent stem cells, we observed impaired erythrocyte production. These findings together with close similarities to published knock-in mouse models of TP53 lacking the CTD demonstrate that the CTD-truncation mutations of TP53 cause IBMFS, providing important insights into the previously postulated connection between p53 and IBMFSs.

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