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1. A case of intestinal T‐cell lymphoma, not otherwise specified, that showed characteristic findings by magnified endoscopy combined with narrow‐band imaging

Author

Hirose, Yuki, primary, Saito, Satoshi, additional, Nishiguchi, Takanori, additional, Yamazaki, Dai, additional, Tateishi, Tsubasa, additional, Saito, Yuuichi, additional, Komeno, Yukiko, additional, Kodama, Makoto, additional, Iwamoto, Shiho, additional, Fukata, Masayuki, additional, and Sako, Minako, additional

Published
2023
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2. SRSF2 Is Essential for Hematopoiesis, and Its Myelodysplastic Syndrome-Related Mutations Dysregulate Alternative Pre-mRNA Splicing

Author

Komeno, Yukiko, Huang, Yi-Jou, Qiu, Jinsong, Lin, Leo, Xu, YiJun, Zhou, Yu, Chen, Liang, Monterroza, Dora D, Li, Hairi, DeKelver, Russell C, Yan, Ming, Fu, Xiang-Dong, and Zhang, Dong-Er

Subjects
Stem Cell Research, Human Genome, Orphan Drug, Rare Diseases, Regenerative Medicine, Genetics, Hematology, Stem Cell Research - Nonembryonic - Non-Human, Cancer, 2.1 Biological and endogenous factors, Aetiology, Blood, Amino Acid Sequence, Animals, Apoptosis, Blood Cells, Bone Marrow Cells, Bone Marrow Transplantation, Cell Line, Cell Survival, HEK293 Cells, Hematopoiesis, Hematopoietic Stem Cells, Humans, Liver, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Myelodysplastic Syndromes, Nuclear Proteins, Poly I-C, RNA Interference, RNA Precursors, RNA Splicing, RNA, Small Interfering, Ribonucleoproteins, Serine-Arginine Splicing Factors, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Myelodysplastic syndromes (MDS) are a group of neoplasms characterized by ineffective myeloid hematopoiesis and various risks for leukemia. SRSF2, a member of the serine/arginine-rich (SR) family of splicing factors, is one of the mutation targets associated with poor survival in patients suffering from myelodysplastic syndromes. Here we report the biological function of SRSF2 in hematopoiesis by using conditional knockout mouse models. Ablation of SRSF2 in the hematopoietic lineage caused embryonic lethality, and Srsf2-deficient fetal liver cells showed significantly enhanced apoptosis and decreased levels of hematopoietic stem/progenitor cells. Induced ablation of SRSF2 in adult Mx1-Cre Srsf2(flox/flox) mice upon poly(I):poly(C) injection demonstrated a significant decrease in lineage(-) Sca(+) c-Kit(+) cells in bone marrow. To reveal the functional impact of myelodysplastic syndromes-associated mutations in SRSF2, we analyzed splicing responses on the MSD-L cell line and found that the missense mutation of proline 95 to histidine (P95H) and a P95-to-R102 in-frame 8-amino-acid deletion caused significant changes in alternative splicing. The affected genes were enriched in cancer development and apoptosis. These findings suggest that intact SRSF2 is essential for the functional integrity of the hematopoietic system and that its mutations likely contribute to development of myelodysplastic syndromes.

Published
2015

3. Runx1 exon 6–related alternative splicing isoforms differentially regulate hematopoiesis in mice

Author

Komeno, Yukiko, Yan, Ming, Matsuura, Shinobu, Lam, Kentson, Lo, Miao-Chia, Huang, Yi-Jou, Tenen, Daniel G, Downing, James R, and Zhang, Dong-Er

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Stem Cell Research - Nonembryonic - Non-Human, Genetics, Stem Cell Research, Hematology, 2.1 Biological and endogenous factors, Aetiology, Animals, Base Sequence, Cells, Cultured, Core Binding Factor Alpha 2 Subunit, Exons, Gene Expression Regulation, HEK293 Cells, Hematopoiesis, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Protein Isoforms, RNA Splice Sites, Sequence Homology, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Paediatrics and Reproductive Medicine, Immunology, Biochemistry and cell biology, Cardiovascular medicine and haematology, Paediatrics
Abstract

RUNX1 is an important transcription factor for hematopoiesis. There are multiple alternatively spliced isoforms of RUNX1. The best known isoforms are RUNX1a from use of exon 7A and RUNX1b and c from use of exon 7B. RUNX1a has unique functions due to its lack of C-terminal regions common to RUNX1b and c. Here, we report that the ortholog of human RUNX1a was only found in primates. Furthermore, we characterized 3 Runx1 isoforms generated by exon 6 alternative splicing. Runx1bEx6(-) (Runx1b without exon 6) and a unique mouse Runx1bEx6e showed higher colony-forming activity than the full-length Runx1b (Runx1bEx6(+)). They also facilitated the transactivation of Runx1bEx6(+). To gain insight into in vivo functions, we analyzed a knock-in (KI) mouse model that lacks isoforms Runx1b/cEx6(-) and Runx1bEx6e. KI mice had significantly fewer lineage-Sca1(+)c-Kit(+) cells, short-term hematopoietic stem cells (HSCs) and multipotent progenitors than controls. In vivo competitive repopulation assays demonstrated a sevenfold difference of functional HSCs between wild-type and KI mice. Together, our results show that Runx1 isoforms involving exon 6 support high self-renewal capacity in vitro, and their loss results in reduction of the HSC pool in vivo, which underscore the importance of fine-tuning RNA splicing in hematopoiesis.

Published
2014

5. SRSF2 Is Essential For Hematopoiesis and Its Mutations Dysregulate Alternative RNA Splicing In MDS

Author

Komeno, Yukiko, Qiu, Jinsong, Lin, Leo, Xu, YiJun, Thol, Felicitas, Monterroza, Dora D, Dekelver, Russell, Chen, Liang, Heuser, Michael, Fu, Xiang-Dong, and Zhang, Dong-Er

Subjects
Stem Cell Research, Stem Cell Research - Nonembryonic - Non-Human, Regenerative Medicine, Rare Diseases, Genetics, Hematology, Human Genome, 2.1 Biological and endogenous factors, Blood, Cancer, Immunology, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Paediatrics and Reproductive Medicine
Abstract

Abstract Myelodysplastic syndromes (MDS) are a group of neoplasms that are ineffective in generating multiple lineages of myeloid cells and have various risks to progress to acute myeloid leukemia. Recent genome-wide sequencing studies reveal that mutations in genes of splicing factors are commonly associated with MDS. However, the importance of these splicing factors in hematopoiesis has been unclear and the causal effect of their mutations on MDS development remains to be determined. One of these newly identified genes is SRSF2, and its mutations have been linked to poor survival among MDS patients. Interestingly, most of SRSF2 mutations occur at proline 95 and the majority of these mutations change this proline to histidine (P95H). Given that SRSF2 is a well-characterized splicing factor involved in both constitutive and regulated splicing, we hypothesize that SRSF2 plays an important role in normal hematopoiesis and the SRSF2 mutations induce specific changes in alternative splicing that favor disease progression. We first examined the role of SRSF2 in hematopoiesis by generating Srsf2 null mutation in mouse blood cells via crossing conditional Srsf2 knockout mice (Srsf2f/f) with blood cell-specific Cre transgenic mice (Vav-Cre). The mutant mice produced significantly fewer definitive blood cells (10% of wild type controls), exhibited increased apoptosis in the remaining blood cells, and died during embryonic development. Importantly, we detected no hematopoietic stem/progenitor cells (lineage-/cKit+) in E14 fetal livers of Vav-Cre/Srsf2f/f mice. These results indicate that SRSF2 is essential for hematopoiesis during embryonic development. We next examined the role of SRSF2 in adult hematopoiesis by injecting polyIC into mice that carry a polyIC inducible Cre expression unit. Unexpectedly, after multiple polyIC treatments, the Srsf2f/f mice stayed alive during several months of observation. Time course genotyping analyses of polyIC treated mice revealed an increased rate of incomplete Srsf2 deletion in peripheral blood cells. These observations suggest that Srsf2 ablation did not cause immediate cell lethality in differentiated blood cells, but the gene is indispensable for the function of blood stem/progenitor cells. Since mutations of splicing factors are generally heterozygous in MDS patients, we also examined mice with Srsf2+/- blood cells. No obvious defect of hematopoiesis was observed under normal conditions or in response to stress with 5-FU treatment and sublethal irradiation. To gain molecular insight into the splicing activity of MDS-associated mutant forms of SRSF2, we performed large-scale alternative splicing surveys by using RNA-mediated oligonucleotide annealing, selection, and ligation coupled with next-generation sequencing (RASL-seq) previously developed in our lab, which offers a robust and cost-effective platform for splicing profiling. Compared to vector transduction controls, we found that overexpression of both wild type and P95H SRSF2 induced many, but distinct changes in alternative splicing in lineage-negative bone marrow cells, and importantly, we noted several changes in genes with known roles in hematopoietic malignancies that were uniquely induced by the mutant SRSF2. To further link the mutations to altered splicing in MDS patients, we also applied RASL-seq to a large number of MDS patient samples with or without mutations in SRSF2 or other splicing regulators. The data revealed a specific set of alternative splicing events that are commonly linked to MDS with splicing factor mutations. These findings strongly suggest that many of these mutations in splicing regulators are gain-of-function mutations that are causal to MDS. In conclusion, we report that SRSF2 plays an essential role in hematopoietic stem/progenitor cells and that the MDS-associated mutations in SRSF2 have a dominant effect on RNA alternative splicing. These findings provide functional information and molecular basis of SRSF2 and its MDS-related mutations in hematopoiesis and related clinical disorders. Disclosures: No relevant conflicts of interest to declare.

Published
2013

6. Cooperation between RUNX1-ETO9a and novel transcriptional partner KLF6 in upregulation of Alox5 in acute myeloid leukemia.

Author

DeKelver, Russell C, Lewin, Benjamin, Lam, Kentson, Komeno, Yukiko, Yan, Ming, Rundle, Chandler, Lo, Miao-Chia, and Zhang, Dong-Er

Subjects
Cell Line, Tumor, Animals, Humans, Mice, Chromosome Aberrations, Arachidonate 5-Lipoxygenase, Oncogene Proteins, Fusion, Proto-Oncogene Proteins, Transcription Factors, Gene Expression Regulation, Leukemic, Alternative Splicing, Core Binding Factor Alpha 2 Subunit, Kruppel-Like Transcription Factors, Leukemia, Myeloid, Acute, Kruppel-Like Factor 6, RUNX1 Translocation Partner 1 Protein, Cell Line, Tumor, Gene Expression Regulation, Leukemic, Leukemia, Myeloid, Acute, Oncogene Proteins, Fusion, Genetics, Developmental Biology
Abstract

Fusion protein RUNX1-ETO (AML1-ETO, RUNX1-RUNX1T1) is expressed as the result of the 8q22;21q22 translocation [t(8;21)], which is one of the most common chromosomal abnormalities found in acute myeloid leukemia. RUNX1-ETO is thought to promote leukemia development through the aberrant regulation of RUNX1 (AML1) target genes. Repression of these genes occurs via the recruitment of the corepressors N-COR and SMRT due to their interaction with ETO. Mechanisms of RUNX1-ETO target gene upregulation remain less well understood. Here we show that RUNX1-ETO9a, the leukemogenic alternatively spliced transcript expressed from t(8;21), upregulates target gene Alox5, which is a gene critically required for the promotion of chronic myeloid leukemia development by BCR-ABL. Loss of Alox5 expression reduces activity of RUNX1-ETO9a, MLL-AF9 and PML-RARα in vitro. However, Alox5 is not essential for the induction of leukemia by RUNX1-ETO9a in vivo. Finally, we demonstrate that the upregulation of Alox5 by RUNX1-ETO9a occurs via the C₂H₂ zinc finger transcription factor KLF6, a protein required for early hematopoiesis and yolk sac development. Furthermore, KLF6 is specifically upregulated by RUNX1-ETO in human leukemia cells. This identifies KLF6 as a novel mediator of t(8;21) target gene regulation, providing a new mechanism for RUNX1-ETO transcriptional control.

Published
2013

7. Atypical Splenic Abscesses Due to Clostridioides difficile

Author

Komeno, Yukiko, primary, Iida, Takeru, additional, Kocha, Ayumu, additional, Kadoma, Naohiro, additional, Ito, Kentaro, additional, Morito, Masaaki, additional, Kodama, Makoto, additional, Abe, Keiko, additional, Ijichi, Masayoshi, additional, and Ryu, Tomiko, additional

Published
2022
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10. Inherited macrothrombocytopenia due to a novel splice donor site mutation in ITGB3.

Author

Komeno, Yukiko, Uchiyama, Toru, Kawano, Fuyuko, Kurihara, Yuya, Kurokawa, Mineo, Ohara, Osamu, Kunishima, Shinji, and Ishiguro, Akira

Subjects
*RECESSIVE genes, *GAIN-of-function mutations, *THROMBOCYTOPENIA, *REVERSE transcriptase polymerase chain reaction
Abstract

Of them, mutations in the guanine base of the splice donor signal dinucleotide GT within intron 13 of I ITGB3 i were found in three families with mild to severe bleeding tendency and macrothrombocytopenia, which followed an autosomal dominant inheritance pattern [[3]]. Blood 139(22):3264-3277. https://pubmed.ncbi.nlm.nih.gov/35167650/ 3 Gresele P, Falcinelli E, Giannini S et al (2009) Dominant inheritance of a novel integrin beta3 mutation associated with a hereditary macrothrombocytopenia and platelet dysfunction in two italian families. Dear Editor, Integrins IIb and 3 form a heterodimeric transmembrane receptor to facilitate platelet aggregation and proplatelet formation [[1]]. [Extracted from the article]

Published
2023
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12. Novel working hypothesis for pathogenesis of hematological malignancies: combination of mutations-induced cellular phenotypes determines the disease (cMIP-DD)

Author

Kitamura, Toshio, Watanabe-Okochi, Naoko, Enomoto, Yutaka, Nakahara, Fumio, Oki, Toshihiko, Komeno, Yukiko, Kato, Naoko, Doki, Noriko, Uchida, Tomoyuki, Kagiyama, Yuki, Togami, Katsuhiro, Kawabata, Kimihito C., Nishimura, Koutarou, Hayashi, Yasutaka, Nagase, Reina, Saika, Makoto, Fukushima, Tsuyoshi, Asada, Shuhei, Fujino, Takeshi, Izawa, Yuto, Horikawa, Sayuri, Fukuyama, Tomofusa, Tanaka, Yosuke, Ono, Ryoichi, Goyama, Susumu, Nosaka, Tetsuya, Kitaura, Jiro, and Inoue, Daichi

Published
2016
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23. Hemophagocytic Syndrome-Associated Variant of Methotrexate-Associated Intravascular Large B-Cell Lymphoma in a Rheumatoid Arthritis Patient

Author

Komeno, Yukiko, Akiyama, Minako, Okochi, Yasumi, Tokuda, Hitoshi, Abe, Keiko, Iihara, Kuniko, and Ryu, Tomiko

Subjects
Article Subject
Abstract

A 59-year-old man was treated for rheumatoid arthritis (RA) for 12 years with methotrexate (MTX) and prednisolone. After MTX-associated interstitial pneumonia developed, he was treated with cyclophosphamide and prednisolone for 7 months. Arthritis worsened, and tacrolimus was added to the treatment regimen. One month later, he had fever, loss of appetite, and dyspnea on exertion. Blood tests showed pancytopenia with large, atypical lymphocytes. Computed tomography showed mild splenomegaly. Bone marrow examination demonstrated CD20-positive, EBER-positive atypical lymphocytes, and hemophagocytosis. Random skin biopsy led to the diagnosis of intravascular large B-cell lymphoma (IVLBCL). The final diagnosis was a hemophagocytic syndrome-associated variant of IVLBCL. Complete remission was achieved after seven courses of R-CHOP. However, within a month, he complained of dizziness. Magnetic resonance imaging revealed focal infarctions in the cerebellum and around the left lateral ventricle. Central nervous system relapse was suspected. Although salvage chemotherapy (CHASER), whole brain irradiation, and intrathecal injection of cytarabine and prednisolone were temporarily effective, he died. Autopsy revealed infiltration of lymphoma cells in the brain and adrenal glands. To the best of our knowledge, this is the sixth case of IVLBCL and the first case of the hemophagocytic syndrome-associated variant of IVLBCL in RA patients in the literature.

Published
2019
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27. Usp18 Is Required for Normal Stem Cell Maintenance

Author

Arimoto, Kei-ichiro, primary, Zhang, Yue, additional, Yan, Ming, additional, Miyauchi, Sayuri, additional, Weng, Stephanie, additional, Stoner, Samuel A., additional, Shima, Takahiro, additional, Komeno, Yukiko, additional, Lam, Kentson, additional, and Zhang, Dong-Er, additional

Published
2016
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29. Novel working hypothesis for pathogenesis of hematological malignancies: combination of mutations-induced cellular phenotypes determines the disease (cMIP-DD)

Author

Kitamura, Toshio, primary, Watanabe-Okochi, Naoko, additional, Enomoto, Yutaka, additional, Nakahara, Fumio, additional, Oki, Toshihiko, additional, Komeno, Yukiko, additional, Kato, Naoko, additional, Doki, Noriko, additional, Uchida, Tomoyuki, additional, Kagiyama, Yuki, additional, Togami, Katsuhiro, additional, Kawabata, Kimihito C., additional, Nishimura, Koutarou, additional, Hayashi, Yasutaka, additional, Nagase, Reina, additional, Saika, Makoto, additional, Fukushima, Tsuyoshi, additional, Asada, Shuhei, additional, Fujino, Takeshi, additional, Izawa, Yuto, additional, Horikawa, Sayuri, additional, Fukuyama, Tomofusa, additional, Tanaka, Yosuke, additional, Ono, Ryoichi, additional, Goyama, Susumu, additional, Nosaka, Tetsuya, additional, Kitaura, Jiro, additional, and Inoue, Daichi, additional

Published
2015
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31. Hes1 promotes blast crisis in chronic myelogenous leukemia through MMP-9 upregulation in leukemic cells

Author

Nakahara, Fumio, primary, Kitaura, Jiro, additional, Uchida, Tomoyuki, additional, Nishida, Chiemi, additional, Togami, Katsuhiro, additional, Inoue, Daichi, additional, Matsukawa, Toshihiro, additional, Kagiyama, Yuki, additional, Enomoto, Yutaka, additional, Kawabata, Kimihito C., additional, Chen-Yi, Lai, additional, Komeno, Yukiko, additional, Izawa, Kumi, additional, Oki, Toshihiko, additional, Nagae, Genta, additional, Harada, Yuka, additional, Harada, Hironori, additional, Otsu, Makoto, additional, Aburatani, Hiroyuki, additional, Heissig, Beate, additional, Hattori, Koichi, additional, and Kitamura, Toshio, additional

Published
2014
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32. The molecular basis of myeloid malignancies

Author

KITAMURA, Toshio, primary, INOUE, Daichi, additional, OKOCHI-WATANABE, Naoko, additional, KATO, Naoko, additional, KOMENO, Yukiko, additional, LU, Yang, additional, ENOMOTO, Yutaka, additional, DOKI, Noriko, additional, UCHIDA, Tomoyuki, additional, KAGIYAMA, Yuki, additional, TOGAMI, Katsuhiro, additional, KAWABATA, Kimihito C., additional, NAGASE, Reina, additional, HORIKAWA, Sayuri, additional, HAYASHI, Yasutaka, additional, SAIKA, Makoto, additional, FUKUYAMA, Tomofusa, additional, IZAWA, Kumi, additional, OKI, Toshihiko, additional, NAKAHARA, Fumio, additional, and KITAURA, Jiro, additional

Published
2014
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33. Expression of the runt homology domain of RUNX1 disrupts homeostasis of hematopoietic stem cells and induces progression to myelodysplastic syndrome

Author

Matsuura, Shinobu, primary, Komeno, Yukiko, additional, Stevenson, Kristen E., additional, Biggs, Joseph R., additional, Lam, Kentson, additional, Tang, Tingdong, additional, Lo, Miao-Chia, additional, Cong, Xiuli, additional, Yan, Ming, additional, Neuberg, Donna S., additional, and Zhang, Dong-Er, additional

Published
2012
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36. Transforming growth factor-β-stimulated clone-22 is a negative-feedback regulator of Ras / Raf signaling: Implications for tumorigenesis

Author

Nakamura, Masaki, primary, Kitaura, Jiro, additional, Enomoto, Yutaka, additional, Lu, Yang, additional, Nishimura, Koutarou, additional, Isobe, Masamichi, additional, Ozaki, Katsutoshi, additional, Komeno, Yukiko, additional, Nakahara, Fumio, additional, Oki, Toshihiko, additional, Kume, Haruki, additional, Homma, Yukio, additional, and Kitamura, Toshio, additional

Published
2011
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37. TIM1 is an endogenous ligand for LMIR5/CD300b: LMIR5 deficiency ameliorates mouse kidney ischemia/reperfusion injury

Author

Yamanishi, Yoshinori, primary, Kitaura, Jiro, additional, Izawa, Kumi, additional, Kaitani, Ayako, additional, Komeno, Yukiko, additional, Nakamura, Masaki, additional, Yamazaki, Satoshi, additional, Enomoto, Yutaka, additional, Oki, Toshihiko, additional, Akiba, Hisaya, additional, Abe, Takaya, additional, Komori, Tadasuke, additional, Morikawa, Yoshihiro, additional, Kiyonari, Hiroshi, additional, Takai, Toshiyuki, additional, Okumura, Ko, additional, and Kitamura, Toshio, additional

Published
2010
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39. AML1 mutations induced MDS and MDS/AML in a mouse BMT model

Author

Watanabe-Okochi, Naoko, primary, Kitaura, Jiro, additional, Ono, Ryoichi, additional, Harada, Hironori, additional, Harada, Yuka, additional, Komeno, Yukiko, additional, Nakajima, Hideaki, additional, Nosaka, Tetsuya, additional, Inaba, Toshiya, additional, and Kitamura, Toshio, additional

Published
2008
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40. Corrigendum to “Antineoplastic effect of a single oral dose of the novel Flt3 inhibitor KRN383 on xenografted human leukemic cells harboring Flt3-activating mutations” [Leuk. Res. 30 (2006) 1541–1546]

Author

Nishiyama, Uichi, primary, Yoshino, Tetsuya, additional, Ozai, Masako, additional, Yoshioka, Rieko, additional, Fujisawa, Motoko, additional, Ogasawara, Yuko, additional, Kitahori, Miyuki, additional, Yoshioka, Eiji, additional, Kubo, Kazuo, additional, Komeno, Yukiko, additional, Kurokawa, Mineo, additional, Ogawa, Seishi, additional, Chiba, Shigeru, additional, Osawa, Tatsushi, additional, Kuwaki, Tomoaki, additional, Hirai, Hisamaru, additional, and Miwa, Atsushi, additional

Published
2007
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41. A Prospective Trial to Evaluate the Safety and Efficacy of Pravastatin for the Treatment of Refractory Chronic Graft-Versus-Host Disease

Author

Hori, Akiko, primary, Kanda, Yoshinobu, additional, Goyama, Susumu, additional, Onishi, Yasushi, additional, Komeno, Yukiko, additional, Mitani, Kinuko, additional, Kishi, Yukiko, additional, Ogawa, Seishi, additional, Imataki, Osamu, additional, Chiba, Shigeru, additional, Kojima, Rie, additional, Hamaki, Tamae, additional, Sakiyama, Michiyo, additional, Kami, Masahiro, additional, Makimoto, Atsushi, additional, Tanosaki, Ryuji, additional, Takaue, Yoichi, additional, and Hirai, Hisamaru, additional

Published
2005
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42. Ki23819 (KRN383•HCl) Inhibits Kinase Activity of Wild Type and Mutant FLT3 Receptor Tyrosine Kinase In Vitro.

Author

Komeno, Yukiko, primary, Kurokawa, Mineo, primary, Imai, Yoichi, primary, Takeshita, Masataka, primary, Matsumura, Tomoko, primary, Kubo, Kazuo, primary, Yoshino, Tetsuya, primary, Nishiyama, Uichi, primary, Kuwaki, Tomoaki, primary, Kubo, Kinya, primary, Osawa, Tatsushi, primary, Ogawa, Seishi, primary, Chiba, Shigeru, primary, Miwa, Atsushi, primary, and Hirai, Hisamaru, primary

Published
2004
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43. Single Oral Administration of KRN383, a Novel Flt3 Inhibitor, Induces Eradication of the Xenograft Tumor Harboring Flt3 Mutation in Mice.

Author

Nishiyama, Uichi, primary, Ozai, Masako, primary, Yoshioka, Rieko, primary, Yoshino, Tetsuya, primary, Ogasawara, Yuko, primary, Kitahori, Miyuki, primary, Yoshioka, Eiji, primary, Kubo, Kazuo, primary, Komeno, Yukiko, primary, Kurokawa, Mineo, primary, Ogawa, Seishi, primary, Chiba, Shigeru, primary, Osawa, Tatsushi, primary, Kuwaki, Tomoaki, primary, Hirai, Hisamaru, primary, and Miwa, Atsushi, primary

Published
2004
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44. Clinical Significance of Peripheral Blood Erythroblastosis after Hematopoietic Stem Cell Transplantation

Author

Goyama, Susumu, primary, Kanda, Yoshinobu, additional, Nannya, Yasuhito, additional, Ogawa, Seishi, additional, Asano-Moki, Yuki, additional, Ogawa, Natsu, additional, Nakagawa, Masahiro, additional, Sakata-Yanagimoto, Mamiko, additional, Kawazu, Masahito, additional, Komeno, Yukiko, additional, Imai, Yoichi, additional, Hangaishi, Akira, additional, Kurokawa, Mineo, additional, Tsujino, Shiho, additional, Aoki, Katsunori, additional, Chiba, Shigeru, additional, Motokura, Toru, additional, and Hirai, Hisamaru, additional

Published
2004
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45. Reduced-intensity bone marrow transplantation from an alternative unrelated donor for myelodysplastic syndrome of first-donor origin

Author

Komeno, Yukiko, primary, Kanda, Yoshinobu, additional, Kandabashi, Koji, additional, Kawazu, Masahito, additional, Goyama, Susumu, additional, Takeshita, Masataka, additional, Nannya, Yasuhito, additional, Niino, Miyuki, additional, Nakamoto, Tetsuya, additional, Kurokawa, Mineo, additional, Tsujino, Shiho, additional, Ogawa, Seishi, additional, Aoki, Katsunori, additional, Chiba, Shigeru, additional, Motokura, Toru, additional, and Hirai, Hisamaru, additional

Published
2003
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46. Ischemic Colitis as a Manifestation of Thrombotic Microangiopathy Following Bone Marrow Transplantation

Author

KOMENO, Yukiko, primary, OGAWA, Seishi, additional, ISHIDA, Tateru, additional, TAKEUCHI, Kengo, additional, TSUJINO, Shiho, additional, KUROKAWA, Mineo, additional, AOKI, Katsunori, additional, KANDA, Yoshinobu, additional, CHIBA, Shigeru, additional, MOTOKURA, Toru, additional, FUKAYAMA, Masashi, additional, and HlRAI, Hisamaru, additional

Published
2003
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47. Rapid diagnosis of invasive pulmonary aspergillosis by quantitative polymerase chain reaction using bronchial lavage fluid

Author

Kawazu, Masahito, primary, Kanda, Yoshinobu, additional, Goyama, Susumu, additional, Takeshita, Masataka, additional, Nannya, Yasuhito, additional, Niino, Miyuki, additional, Komeno, Yukiko, additional, Nakamoto, Tetsuya, additional, Kurokawa, Mineo, additional, Tsujino, Shiho, additional, Ogawa, Seishi, additional, Aoki, Katsunori, additional, Chiba, Shigeru, additional, Motokura, Toru, additional, Ohishi, Nobuya, additional, and Hirai, Hisamaru, additional

Published
2002
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49. Cooperation between RUNX1-ETO9a and Novel Transcriptional Partner KLF6 in Upregulation of Alox5 in Acute Myeloid Leukemia.

Author

DeKelver, Russell C., Lewin, Benjamin, Lam, Kentson, Komeno, Yukiko, Yan, Ming, Rundle, Chandler, Lo, Miao-Chia, and Zhang, Dong-Er

Subjects
CHIMERIC proteins, ACUTE myeloid leukemia treatment, GENETIC regulation, HEMATOPOIETIC stem cells, ANIMAL models in research, MICE
Abstract

Fusion protein RUNX1-ETO (AML1-ETO, RUNX1-RUNX1T1) is expressed as the result of the 8q22;21q22 translocation [t(8;21)], which is one of the most common chromosomal abnormalities found in acute myeloid leukemia. RUNX1-ETO is thought to promote leukemia development through the aberrant regulation of RUNX1 (AML1) target genes. Repression of these genes occurs via the recruitment of the corepressors N-COR and SMRT due to their interaction with ETO. Mechanisms of RUNX1-ETO target gene upregulation remain less well understood. Here we show that RUNX1-ETO9a, the leukemogenic alternatively spliced transcript expressed from t(8;21), upregulates target gene Alox5, which is a gene critically required for the promotion of chronic myeloid leukemia development by BCR-ABL. Loss of Alox5 expression reduces activity of RUNX1-ETO9a, MLL-AF9 and PML-RARα in vitro. However, Alox5 is not essential for the induction of leukemia by RUNX1-ETO9a in vivo. Finally, we demonstrate that the upregulation of Alox5 by RUNX1-ETO9a occurs via the C2H2 zinc finger transcription factor KLF6, a protein required for early hematopoiesis and yolk sac development. Furthermore, KLF6 is specifically upregulated by RUNX1-ETO in human leukemia cells. This identifies KLF6 as a novel mediator of t(8;21) target gene regulation, providing a new mechanism for RUNX1-ETO transcriptional control. [ABSTRACT FROM AUTHOR]

Published
2013
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50. Enhanced expression of p210BCR/ABLand aberrant expression of Zfp423/ZNF423induce blast crisis of chronic myelogenous leukemia

Author

Miyazaki, Kazuko, Yamasaki, Norimasa, Oda, Hideaki, Kuwata, Takeshi, Kanno, Yohei, Miyazaki, Masaki, Komeno, Yukiko, Kitaura, Jiro, Honda, Zen-ichiro, Warming, Søren, Jenkins, Nancy A., Copeland, Neal G., Kitamura, Toshio, Nakamura, Takuro, and Honda, Hiroaki

Abstract

Chronic myelogenous leukemia (CML) is a hematopoietic disorder originating from p210BCR/ABL-transformed stem cells, which begins as indolent chronic phase (CP) but progresses into fatal blast crisis (BC). To investigate molecular mechanism(s) underlying disease evolution, CML-exhibiting p210BCR/ABLtransgenic mice were crossed with BXH2 mice that transmit a replication-competent retrovirus. Whereas nontransgenic mice in the BXH2 background exclusively developed acute myeloid leukemia, p210BCR/ABLtransgenic littermates developed nonmyeloid leukemias, in which inverse polymerase chain reaction detected 2 common viral integration sites (CISs). Interestingly, one CIS was transgene’s own promoter, which up-regulated p210BCR/ABLexpression. The other was the 5′ noncoding region of a transcription factor, Zfp423, which induced aberrant Zfp423expression. The cooperative activities of Zfp423and p210BCR/ABLwere demonstrated as follows: (1) introduction of Zfp423in p210BCR/ABLtransgenic bone marrow (BM) cells increased colony-forming ability, (2) suppression of ZNF423(human homologue of Zfp423) in ZNF423-expressing, p210BCR/ABL-positive hematopoietic cells retarded cell growth, (3) mice that received a transplant of BM cells transduced with Zfp423and p210BCR/ABLdeveloped acute leukemia, and (4) expression of ZNF423was found in human BCR/ABL-positive cell lines and CML BC samples. These results demonstrate that enhanced expression of p210BCR/ABLand deregulated expression of Zfp423/ZNF423contribute to CML BC.

Published
2009
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