Publications by authors named "Minenori Eguchi-Ishimae"

32 Publications

A Catheter-Related Bloodstream Infection by in a Child with Acute Myeloid Leukemia: Case Report and Literature Review.

Case Rep Pediatr 2021 9;2021:6691569. Epub 2021 Apr 9.

Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan.

The most common organisms isolated from pediatric catheter-related bloodstream infections (CRBSIs) are Gram-positive cocci, such as coagulase-negative staphylococci and . There are few formal reports of infection and even fewer reports of CRBSI due to this Gram-positive rod. Here we report the first case of CRBSI due to in an 8-year-old girl with acute myeloid leukemia in Japan. The isolate exhibited decreased susceptibility to -lactam antibiotics. Antimicrobial therapy with meropenem and vancomycin, in addition to the removal of central venous catheter line, consequently led to a significant clinical improvement of the patient's symptoms. A literature review found available clinical courses in 16 cases (4 pediatric cases including our case) of infection. Our case and those in literature suggested that infection often occurs in patients with indwelling central venous catheters; the literature review further suggested that removal of central venous catheters is required in most cases. Special attention should be paid to the detection of opportunistic infections due to spp. in immunocompromized children who are using a central venous catheter.
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http://dx.doi.org/10.1155/2021/6691569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052168PMC
April 2021

Malignant Ovarian Steroid Cell Tumor, Not Otherwise Specified, Causes Virilization in a 4-Year-Old Girl: A Case Report and Literature Review.

Case Rep Oncol 2020 Jan-Apr;13(1):358-364. Epub 2020 Apr 2.

Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Japan.

We report a case of a 4-year-old girl with an ovarian steroid cell tumor, not otherwise specified (SCT-NOS). She was admitted to the hospital with progressing virilization and Cushing's syndrome, which included abnormality of the perineum, hirsutism, hypertrichosis, flushing of face, hoarseness, and weight gain. Blood testing showed a significantly increased testosterone level and slightly increased cortisol level. Computed tomography scan revealed an 8.0 × 5.0 × 5.0 cm tumor of the right ovary. The patient underwent right salpingo-oophorectomy, and pathological examination showed malignant potential. Three courses of bleomycin, etoposide, and cisplatin were administered as postoperative chemotherapy. After tumor resection, her testosterone decreased to undetectable levels. However, during the course of the treatment, the patient suffered from adrenal insufficiency resulting in the need for hydrocortisone replacement therapy. Although SCT-NOS in childhood are typically benign, pathological findings should be carefully observed for potential malignancy. In cases of cortisol-producing SCT-NOS, serum levels should be monitored, and hydrocortisone replacement therapy should be considered before resection.
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http://dx.doi.org/10.1159/000506044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184839PMC
April 2020

Brain Abscess Associated with Polymicrobial Infection after Intraoral Laceration: A Pediatric Case Report.

Case Rep Pediatr 2020 9;2020:8304302. Epub 2020 Mar 9.

Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

Brain abscesses, infections within the brain parenchyma, can arise as complications of various conditions including infections, trauma, and surgery. However, brain abscesses due to polymicrobial organisms have rarely been reported in children. We herein report a case of a 9-year-old girl with unresolved congenital cyanotic heart disease (CCHD) presenting with right hemiplegia who was diagnosed with brain abscess caused by , , and after oropharyngeal injury. She was treated with intravenous antimicrobial therapy, drainage under craniotomy, and antiedema therapy with glycerol and goreisan, which led to the improvement of right hemiplegia to baseline; she was discharged following eight weeks of intravenous antimicrobial therapy. The clinical diagnosis of the brain abscess was difficult due to the nonspecific presentation, highlighting the importance of cranial imaging without haste in patients at increased risk for brain abscesses such as those with CCHD, presenting with fever in the absence of localizing symptoms or fever, accompanied with abnormal neurological findings.
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http://dx.doi.org/10.1155/2020/8304302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085370PMC
March 2020

Mesenchymal Stem Cell Therapy Overcomes Steroid Resistance in Severe Gastrointestinal Acute Graft-Versus-Host Disease.

Case Rep Transplant 2019 21;2019:7890673. Epub 2019 May 21.

Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan.

The authors describe the high effectiveness of human mesenchymal stem cell (hMSC) therapy to treat steroid-refractory gastrointestinal acute graft-versus-host Disease (aGVHD) in a 15-year-old boy with acute lymphoblastic leukemia (ALL). He received allogeneic hematopoietic stem cell transplantation due to high-risk hypodiploid ALL. Around the time of engraftment, he developed severe diarrhea following high-grade fever and erythema. Although methylprednisolone pulse therapy was added to tacrolimus and mycophenolate mofetil, diarrhea progressed up to 5000~6000 ml/day and brought about hypocalcemia, hypoalbuminemia, and edema. Daily fresh frozen plasma (FFP), albumin, and calcium replacements were required to maintain blood circulation. After aGVHD was confirmed by colonoscopic biopsy, MSC therapy was administered. The patient received 8 biweekly intravenous infusions of 2×10 hMSCs/kg for 4 weeks, after which additional 4 weekly infusions were performed. A few weeks after initiation, diarrhea gradually resolved, and at the eighth dose of hMSC, lab data improved without replacements. MSC therapy successfully treated steroid-refractory gastrointestinal GVHD without complications. Despite life-threatening diarrhea, the regeneration potential of children and adolescents undergoing SMC therapy successfully supports restoration of gastrointestinal damage. Even with its high treatment costs, SMC therapy should be proactively considered in cases where young patients suffer from severe gastrointestinal GVHD.
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http://dx.doi.org/10.1155/2019/7890673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556259PMC
May 2019

Early detection of the PAX3-FOXO1 fusion gene in circulating tumor-derived DNA in a case of alveolar rhabdomyosarcoma.

Genes Chromosomes Cancer 2019 08 10;58(8):521-529. Epub 2019 Feb 10.

Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

Cell-free DNA (cfDNA), which are small DNA fragments in blood derived from dead cells including tumor cells, could serve as useful biomarkers and provide valuable genetic information about the tumors. cfDNA is now used for the genetic analysis of several types of cancers, as a surrogate for tumor biopsy, designated as "liquid biopsy." Rhabdomyosarcoma (RMS), the most frequent soft tissue tumor in childhood, can arise in any part of the body, and radiological imaging is the only available method for estimating the tumor burden, because no useful specific biological markers are present in the blood. Because tumor volume is one of the determinants of treatment response and outcome, early detection at diagnosis as well as relapse is essential for improving the treatment outcome. A 15-year-old male patient was diagnosed with alveolar RMS of prostate origin with bone marrow invasion. The PAX3-FOXO1 fusion was identified in the tumor cells in the bone marrow. After the diagnosis, cfDNA was serially collected to detect the PAX3-FOXO1 fusion sequence as a tumor marker. cfDNA could be an appropriate source for detecting the fusion gene; assays using cfDNA have proved to be useful for the early detection of tumor progression/recurrence. Additionally, the fusion gene dosage estimated by quantitative polymerase chain reaction reflected the tumor volume during the course of the treatment. We suggest that for fusion gene-positive RMSs, and other soft tissue tumors, the fusion sequence should be used for monitoring the tumor burden in the body to determine the diagnosis and treatment options for the patients.
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http://dx.doi.org/10.1002/gcc.22734DOI Listing
August 2019

Exon skipping in CYBB mRNA and skewed inactivation of X chromosome cause late-onset chronic granulomatous disease.

Pediatr Hematol Oncol 2018 Aug - Sep;35(5-6):341-349. Epub 2019 Jan 11.

a Department of Pediatrics , Ehime University Graduate School of Medicine , Toon , Ehime , Japan.

Chronic granulomatous disease (CGD) is a hereditary immunodeficiency syndrome caused by a defect in the NADPH oxidase complex, which is essential for bactericidal function of phagocytes. Approximately 70% of patients with CGD have a mutation in the CYBB gene on the X chromosome, resulting in defective expression of gp91, one of the membrane-bound subunits of NADPH oxidase. Although most patients with X-linked CGD are males, owing to transmission of this disease as an X-linked recessive trait, there are female patients with X-linked CGD. Here, we report the case of a teenage girl with X-linked CGD associated with a heterozygous mutation in exon 5 of the CYBB gene (c.389G > C; R130P), which causes skipping of exon 5, resulting in a premature stop codon in exon 6 of CYBB. Accurate pro-mRNA splicing for mature mRNA formation is regulated by several splicing mechanisms that are essential for appropriate recognition of exonic sequences. The c.389G > C mutation disrupts exonic-splicing regulator sequences, thereby resulting in the aberrant skipping of exon 5 in the CYBB transcript of the patient. The patient showed an extremely skewed (≥96%) X inactivation pattern of the HUMARA locus; this inactivation is thought to be responsible for the development of CGD not only in neutrophils but also in monocytic, T-cell, and B-cell lineages and in CD34-positive immature hematopoietic cells. Our case and other reports indicate that the onset of X-linked CGD in female patients tends to occur later in life, and that the symptoms tend to be milder as compared to male patients.
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http://dx.doi.org/10.1080/08880018.2018.1522402DOI Listing
March 2019

Prolonged adrenal insufficiency after high-dose glucocorticoid in infants with leukemia.

Pediatr Hematol Oncol 2018 Aug - Sep;35(5-6):355-361. Epub 2018 Nov 20.

a Department of Pediatrics , Ehime University Graduate School of Medicine , Ehime , Japan.

Although outcomes for infant leukemia have improved recently, transient adrenal insufficiency is commonly observed during treatment, especially after glucocorticoid administration. We identified three infants with acute leukemia who suffered from prolonged adrenal insufficiency requiring long-term (from 15 to 66 months) hydrocortisone replacement. All infants showed life-threatening symptoms associated with adrenal crisis after viral infections or other stress. Severe and prolonged damage of hypothalamo-pituitary-adrenal (HPA) axis is likely to occur in early infants with leukemia, therefore routine tolerance testing to evaluate HPA axis and hydrocortisone replacement therapy are recommended for infants with leukemia to avoid life-threatening complications caused by adrenal crisis.
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http://dx.doi.org/10.1080/08880018.2018.1539148DOI Listing
March 2019

Usefulness of positron emission tomography-CT for diagnosis of primary bone marrow lymphoma in children.

Pediatr Hematol Oncol 2018 Mar 12;35(2):125-130. Epub 2018 Apr 12.

a Department of Pediatrics , Ehime University Graduate School of Medicine , Ehime , Japan.

Primary bone marrow lymphoma (PBML) is hard to diagnose in children, due to the difficult identification of malignant cells in bone marrow. The first case, a 5-year-old boy, showed knee swelling with an intermittent fever. The second case, a 12-year-old girl, showed fever of unknown origin without lymphadenopathy or hepatosplenomegaly. In both cases, the diagnosis was not confirmed despite the repeated bone marrow aspirations. Finally, bone marrow aspiration and biopsy at the positive site by positron emission tomography (PET)-CT contributed to definitive diagnosis of PBML. The PET-CT is useful for the accurate diagnosis of PBML in children with non-specific symptoms.
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http://dx.doi.org/10.1080/08880018.2018.1459984DOI Listing
March 2018

Manifestation of recessive combined D-2-, L-2-hydroxyglutaric aciduria in combination with 22q11.2 deletion syndrome.

Am J Med Genet A 2018 02 19;176(2):351-358. Epub 2017 Dec 19.

Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

22q11.2 deletion syndrome is one of the most common human microdeletion syndromes. The clinical phenotype of 22q11.2 deletion syndrome is variable, ranging from mild to life-threatening symptoms, depending mainly on the extent of the deleted region. Brain malformations described in association with 22q11.2 deletion syndrome include polymicrogyria, cerebellar hypoplasia, megacisterna magna, and agenesis of the corpus callosum (ACC), although these are rare. We report here for the first time a patient who manifested combined D-2- and L-2-hydroxyglutaric aciduria as a result of a hemizygous mutation in SLC25A1 in combination with 22q11.2 deletion. The girl was diagnosed to have ACC shortly after birth and a deletion of 22q11.2 was identified by genetic analysis. Although the patient showed cardiac anomalies, which is one of the typical symptoms of 22q11.2 deletion syndrome, her rather severe phenotype and atypical face prompted us to search for additional pathogenic mutations. Three genes present in the deleted 22q11.2 region, SLC25A1, TUBA8, and SNAP29, which have been reported to be associated with brain malformation, were analyzed for the presence of pathogenic mutations. A frameshift mutation, c.18_24dup (p.Ala9Profs*82), was identified in the first exon of the remaining SLC25A1 allele, resulting in the complete loss of normal SLC25A1 function in the patient's cells. Our results support the notion that the existence of another genetic abnormality involving the retained allele on 22q11.2 should be considered when atypical or rare phenotypes are observed.
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http://dx.doi.org/10.1002/ajmg.a.38578DOI Listing
February 2018

[Leukemia].

Gan To Kagaku Ryoho 2016 Nov;43(11):1341-1345

Dept. of Pediatrics, Ehime University Graduate School of Medicine.

Leukemia is derived from hematopoietic stem/progenitor cells that have acquired genetic abnormalities, leading to malignant transformation. The basis of therapyfor leukemia is a combination of anti-cancer drugs based on risk stratification. The overall 5-year survival rate in leukemia patients of all ages is still 40%, although it has improved in pediatric patients. Leuke- mia itself is a heterogeneous disease that includes various entities/subtypes with different pathogenic gene aberrations. Selection of the treatment strategylargelydepends on risk stratification, and this in turn is mainlybased on specific recurrent chromosome aberrations. However, in acute myeloid leukemia(AML), a significant proportion of patients present with a normal karyotype according to conventional cytogenetic analysis and are classified into an intermediate-risk group, which actuallyconsists of various subtypes with different prognoses. In addition, leukemic cells usuallyharbor one or more driver mutations among their various genetic aberrations, and these driver mutations could affect prognosis. The discoveryof additional mutations in genes such as NPM1, CEBPA and FLT3, which are frequent in AML patients with a normal karyotype, have improved the precision of risk stratification in AML. In this regard, array-based gene expression analysis and whole exome/ transcriptome sequencing could be useful tools for identifying the whole spectrum of genetic aberrations, or for compiling a complete list of mutated genes within leukemic cells. Genetic profiling information obtained using these newlydeveloped methods could provide more accurate information for molecular subtyping and risk stratification in leukemia.
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November 2016

Installation of multiple automated external defibrillators to prevent sudden death in school-aged children.

Pediatr Int 2016 Dec 10;58(12):1261-1265. Epub 2016 Nov 10.

Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

Background: Recently, a student died of idiopathic ventricular fibrillation in a school where an automated external defibrillator (AED) had been installed. The tragedy could not be prevented because the only AED in the school was installed in the teachers' office, far from the school ground where the accident took place. This prompted establishment of a multiple AED system in schools. The aim of this study was to analyze the efficacy of the multiple AED system to prevent sudden death in school-aged children.

Methods: Assumed accident sites consisted of the school ground, gymnasium, Judo and Kendo hall, swimming pool, and classrooms on the first and the fourth floor. Multiple AED were installed in the teachers' office, gymnasium, some classrooms, and also provided as a portable AED in a rucksack. The time from the accident site to the teachers' office for single AED, and from the accident site to the nearest AED for multiple AED, was calculated.

Results: The AED retrieval time was significantly shorter in 55 elementary schools and in 29 junior high schools when multiple AED were installed compared with single AED. Except for the classroom on the fourth floor, the number of people who took >120 s to bring the AED to the accident site was lower when multiple AED were installed compared with the single AED.

Conclusion: Multiple AED provided in appropriate sites can reduce the time to reach the casualty and hence prevent sudden death in school-aged children.
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http://dx.doi.org/10.1111/ped.13143DOI Listing
December 2016

[Recent progress in leukemic stem cell research for childhood leukemia].

Rinsho Ketsueki 2015 Oct;56(10):1871-81

Department of Pediatrics, Ehime University Graduate School of Medicine.

Leukemic stem cells (LSCs) were originally identified in acute myeloid leukemia (AML) cases by using xenograft models, as a distinct cell population that can initiate leukemia in immunodeficient mice. Since then, many efforts have been made to clarify the identities of LSCs and other cancer stem cells in various cancer types, to both understand their biology and determine the most suitable targets for anti-cancer therapies. LSCs were identified as existing in the immature CD34+CD38- leukemic population in most AML cases, and these cells were found to share some features with normal hematopoietic stem cells. On the other hand, recent studies have shown that in childhood acute lymphoblastic leukemia (ALL), LSCs exist among B-lineage-committed progenitors expressing CD19. In contrast to AML, in which LSCs generate leukemic cells in a hierarchical order with LSCs at the top, leukemia propagation in childhood ALL is better explained by a stochastic model. In B-precursor ALL, LSCs form via acquisition of additional genetic change(s) in CD19+ B-lineage progenitor cells with self-renewing capacity. These LSCs possess a growth advantage and the capacity to produce progeny with the same ability as the LSCs. Identification of genetic and cellular targets in leukemic transformation is necessary to develop improved anti-cancer therapies.
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http://dx.doi.org/10.11406/rinketsu.56.1871DOI Listing
October 2015

HMGA2 as a potential molecular target in KMT2A-AFF1-positive infant acute lymphoblastic leukaemia.

Br J Haematol 2015 Dec 25;171(5):818-29. Epub 2015 Sep 25.

Department of Paediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

Acute lymphoblastic leukaemia (ALL) in infants is an intractable cancer in childhood. Although recent intensive chemotherapy progress has considerably improved ALL treatment outcome, disease cure is often accompanied by undesirable long-term side effects, and efficient, less toxic molecular targeting therapies have been anticipated. In infant ALL cells with KMT2A (MLL) fusion, the microRNA let-7b (MIRLET7B) is significantly downregulated by DNA hypermethylation of its promoter region. We show here that the expression of HMGA2, one of the oncogenes repressed by MIRLET7B, is reversely upregulated in infant ALL leukaemic cells, particularly in KMT2A-AFF1 (MLL-AF4) positive ALL. In addition to the suppression of MIRLET7B, KMT2A fusion proteins positively regulate the expression of HMGA2. HMGA2 is one of the negative regulators of CDKN2A gene, which encodes the cyclin-dependent kinase inhibitor p16(INK4A) . The HMGA2 inhibitor netropsin, when combined with demethylating agent 5-azacytidine, upregulated and sustained the expression of CDKN2A, which resulted in growth suppression of KMT2A-AFF1-expressing cell lines. This effect was more apparent compared to treatment with 5-azacytidine alone. These results indicate that the MIRLET7B-HMGA2-CDKN2A axis plays an important role in cell proliferation of leukaemic cells and could be a possible molecular target for the therapy of infant ALL with KMT2A-AFF1.
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http://dx.doi.org/10.1111/bjh.13763DOI Listing
December 2015

DGCR6 at the proximal part of the DiGeorge critical region is involved in conotruncal heart defects.

Hum Genome Var 2015 12;2:15004. Epub 2015 Feb 12.

Department of Pediatrics, Ehime University Graduate School of Medicine , Toon, Ehime, Japan.

Cardiac anomaly is one of the hallmarks of DiGeorge syndrome (DGS), observed in approximately 80% of patients. It often shows a characteristic morphology, termed as conotruncal heart defects. In many cases showing only the conotruncal heart defect, deletion of 22q11.2 region cannot be detected by fluorescence in situ hybridization (FISH), which is used to detect deletion in DGS. We investigated the presence of genomic aberrations in six patients with congenital conotruncal heart defects, who show no deletion at 22q11.2 in an initial screening by FISH. In these patients, no abnormalities were identified in the coding region of the TBX1 gene, one of the key genes responsible for the phenotype of DGS. However, when copy number alteration was analyzed by high-resolution array analysis, a small deletion or duplication in the proximal end of DiGeorge critical region was detected in two patients. The affected region contains the DGCR6 and PRODH genes. DGCR6 has been reported to affect the expression of the TBX1 gene. Our results suggest that altered dosage of gene(s) other than TBX1, possibly DGCR6, may also be responsible for the development of conotruncal heart defects observed in patients with DGS and, in particular, in those with stand-alone conotruncal heart defects.
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http://dx.doi.org/10.1038/hgv.2015.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785558PMC
April 2016

Identification of CD34+ and CD34- leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia.

Blood 2015 Feb 23;125(6):967-80. Epub 2014 Dec 23.

Laboratory for Human Disease Models RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;

Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia-initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34(+)CD38(+)CD19(+) and CD34(-)CD19(+) cells initiated leukemia, and in MLL-AF9 patients, CD34(-)CD19(+) cells were LICs. In MLL-ENL patients, either CD34(+) or CD34(-) cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34(+)CD38(-)CD19(-)CD33(-) cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34(+)CD38(-)CD19(-)CD33(-) cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4(+) single positive (SP), CD8(+) SP, and CD4(+)CD8(+) double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34(+)CD38(+) and CD34(-) LICs but not in CD34(+)CD38(-)CD19(-)CD33(-) HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia.
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http://dx.doi.org/10.1182/blood-2014-03-563304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319237PMC
February 2015

Lineage-dependent skewing of loss of heterozygosity (LOH) of KRAS gene in a case of juvenile myelomonocytic leukemia.

Eur J Haematol 2015 Feb 17;94(2):177-81. Epub 2014 May 17.

Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan.

Juvenile myelomonocytic leukemia (JMML) is a clonal disease arising from abnormal hematopoietic stem cells, although the involvement of lymphoid lineage differs among reported cases. Here, we present a case of JMML with a KRAS G13D mutation. The mutation was detected in various hematopoietic lineages, including T and B lymphocytes and also in lineage(-) CD34(+) CD38(-) hematopoietic stem cells, showing a different percentage of affected cells in each lineage. Single cell-based analysis of hematopoietic cells revealed the loss of wild-type KRAS in a significant proportion of G13D-harboring cells. The percentage of loss of heterozygosity (LOH)/non-LOH cells showed lineage-dependent skewing in hematopoietic cells. The loss of the wild-type KRAS allele may be a common secondary genetic change in KRAS-related JMML and may affect the differentiation behavior of early JMML progenitors.
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http://dx.doi.org/10.1111/ejh.12355DOI Listing
February 2015

CLTC-ALK fusion as a primary event in congenital blastic plasmacytoid dendritic cell neoplasm.

Genes Chromosomes Cancer 2014 Jan 21;53(1):78-89. Epub 2013 Oct 21.

Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a subtype of acute myeloid leukemia, affecting mainly the elderly. It is thought to be derived from plasmacytoid dendritic cell precursors, which frequently present as cutaneous lesions. We have made a detailed analysis of an infant with BPDCN, who manifested with hemophagocytic lymphohistiocytosis. The peripheral blood leukocytes revealed the t(2;17;8)(p23;q23;p23) translocation and a CLTC-ALK fusion gene, which have never been reported in BPDCN or in any myeloid malignancies thus far. Neonatal blood spots on the patient's Guthrie card were analyzed for the presence of the CLTC-ALK fusion gene, identifying the in utero origin of the leukemic cell. Although the leukemic cells were positive for CD4, CD56, CD123, and CD303, indicating a plasmacytoid dendritic cell phenotype, detailed analysis of the lineage distribution of CLTC-ALK revealed that part of monocytes, neutrophils, and T cells possessed the fusion gene and were involved in the leukemic clone. These results indicated that leukemic cells with CLTC-ALK originated in a multipotent hematopoietic progenitor in utero. This is the first report of the CLTC-ALK fusion gene being associated with a myeloid malignancy, which may give us an important clue to the origin of this rare neoplasm.
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http://dx.doi.org/10.1002/gcc.22119DOI Listing
January 2014

Novel dominant-negative mutant of GATA3 in HDR syndrome.

J Mol Med (Berl) 2011 Jan 1;89(1):43-50. Epub 2010 Dec 1.

Department of Neonatology, Maternity & Perinatal Care Unit, Ehime University Hospital, Shitsukawa, Toon, Matsuyama, Ehime, 791-0295, Japan.

HDR syndrome is an autosomal dominant disorder characterized by hypoparathyroidism, sensorineural deafness, and renal anomaly caused by mutation of the GATA3 gene located at chromosome 10p15. We report the case of a neonate with HDR syndrome and a novel GATA3 mutation. We performed genetic and functional analysis of GATA3 in this patient and identified a novel heterozygous 1516G> C missense mutation in exon 5, resulting in a cysteine-to-serine substitution at codon 321 (Cys321Ser). Mutated and wild-type GATA3 proteins were expressed at a similar level in vitro, indicating that the mutated GATA3 protein was stable. Luciferase assay revealed that the Cys321Ser-mutated GATA3 lacked transactivation activity due to loss of DNA-binding activity as confirmed by gel shift assay. Moreover, mutated GATA3 exerted a dominant-negative effect over the transactivation activity of wild-type GATA3. These findings indicate that not only haploinsufficiency of GATA3 but also the dominant-negative effect of Cys321Ser-mutated GATA3 might have been responsible for the HDR syndrome phenotype of our patient.
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http://dx.doi.org/10.1007/s00109-010-0702-6DOI Listing
January 2011

ETV6-ARNT fusion in a patient with childhood T lymphoblastic leukemia.

Cancer Genet Cytogenet 2010 Oct;202(1):22-6

Department of Pediatrics, University of Toyama, Japan.

The ETS variant gene 6 (ETV6) gene is located at 12p13, and is frequently involved in translocations in various human neoplasms, resulting in the expression of fusion proteins consisting of the amino-terminal part of ETV6 and unrelated transcription factors or protein tyrosine kinases. Leukemia with t(1;12)(q21;p13) was previously described in a 5-year-old boy with acute myeloblastic leukemia (AML-M2) who exhibited a novel ETV6-aryl hydrocarbon receptor nuclear translocator (ARNT) fusion protein. We herein report the case of a 2-year-old boy with T-cell lymphoblastic leukemia (T-ALL) harboring t(1;12)(q21;p13). Fluorescence in situ hybridization (FISH) with a ETV6 dual-color DNA probe revealed that the split signals of the ETV6 gene in 96.7% of bone marrow cells, indicating rearrangement of the ETV6 gene. Therefore, we performed a FISH analysis with bacterial artificial chromosome (BAC) probes containing the ARNT, BCL9, and MLLT11 genes located at 1q21, and these results indicated that the ARNT gene might be involved in the t(1;12)(q21;p13). Reverse transcriptase-polymerase chain reaction analysis disclosed the existence of a ETV6-ARNT fusion gene. To our knowledge, the current report is novel in its report of the ETV6-ARNT fusion in childhood T-ALL. The ETV6-ARNT fusion is associated not only with AML but also with T-ALL.
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http://dx.doi.org/10.1016/j.cancergencyto.2010.07.121DOI Listing
October 2010

Leukemia-related transcription factor TEL/ETV6 expands erythroid precursors and stimulates hemoglobin synthesis.

Cancer Sci 2009 Apr 11;100(4):689-97. Epub 2009 Mar 11.

Department of Hematology, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan.

TEL/ETV6 located at chromosome 12p13 encodes a member of the E26 transformation-specific family of transcription factors. TEL is known to be rearranged in a variety of leukemias and solid tumors resulting in the formation of oncogenic chimeric protein. Tel is essential for maintaining hematopoietic stem cells in the bone marrow. To understand the role of TEL in erythropoiesis, we generated transgenic mice expressing human TEL under the control of Gata1 promoter that is activated during the course of the erythroid-lineage differentiation (GATA1-TEL transgenic mice). Although GATA1-TEL transgenic mice appeared healthy up to 18 months of age, the level of hemoglobin was higher in transgenic mice compared to non-transgenic littermates. In addition, CD71+/TER119+ and c-kit+/CD41+ populations proliferated with a higher frequency in transgenic mice when bone marrow cells were cultured in the presence of erythropoietin and thrombopoietin, respectively. In transgenic mice, enhanced expression of Alas-e and beta-major globin genes was observed in erythroid-committed cells. When embryonic stem cells expressing human TEL under the same Gata1 promoter were differentiated into hematopoietic cells, immature erythroid precursor increased better compared to controls as judged from the numbers of burst-forming unit of erythrocytes. Our findings suggest some roles of TEL in expanding erythroid precursors and accumulating hemoglobin.
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http://dx.doi.org/10.1111/j.1349-7006.2009.01097.xDOI Listing
April 2009

Enhanced expression of the EVI1 gene in NUP98/HOXA-expressing leukemia cells.

Int J Hematol 2009 Mar 26;89(2):253-256. Epub 2009 Feb 26.

Department of Hematology, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi-ken, 321-0293, Japan.

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http://dx.doi.org/10.1007/s12185-009-0267-8DOI Listing
March 2009

Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia.

Blood 2009 Jan 16;113(3):646-8. Epub 2008 Oct 16.

Section of Haemato-Oncology, The Institute of Cancer Research, Sutton, United Kingdom.

Children with Down syndrome (DS) have a greatly increased risk of acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (ALL). Both DS-AMKL and the related transient myeloproliferative disorder (TMD) have GATA1 mutations as obligatory, early events. To identify mutations contributing to leukemogenesis in DS-ALL, we undertook sequencing of candidate genes, including FLT3, RAS, PTPN11, BRAF, and JAK2. Sequencing of the JAK2 pseudokinase domain identified a specific, acquired mutation, JAK2R683, in 12 (28%) of 42 DS-ALL cases. Functional studies of the common JAK2R683G mutation in murine Ba/F3 cells showed growth factor independence and constitutive activation of the JAK/STAT signaling pathway. High-resolution SNP array analysis of 9 DS-ALL cases identified additional submicroscopic deletions in key genes, including ETV6, CDKN2A, and PAX5. These results infer a complex molecular pathogenesis for DS-ALL leukemogenesis, with trisomy 21 as an initiating or first hit and with chromosome aneuploidy, gene deletions, and activating JAK2 mutations as complementary genetic events.
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http://dx.doi.org/10.1182/blood-2008-08-170928DOI Listing
January 2009

Clinical features and outcome of MLL gene rearranged acute lymphoblastic leukemia in infants with additional chromosomal abnormalities other than 11q23 translocation.

Leuk Res 2008 Oct 29;32(10):1523-9. Epub 2008 Apr 29.

Department of Pediatrics, Ehime University, Toon, Ehime, Japan.

The treatment outcome for infant acute lymphoblastic leukemia (ALL) with positive MLL gene rearrangements remains poor. We analyzed whether additional chromosomal abnormalities (ACA) other than 11q23 translocation could affect the disease behavior and its prognosis. Eighteen of seventy-four patients with infant acute lymphoblastic leukemia showed ACA, including three-way translocations in four, other novel translocations in four, and complex structural chromosomal changes in four. Only age less than 6 months and positive central nervous system leukemia were significant prognostic factors by multivariate analysis. However, overall survival rates were worse in patients with ACA compared to those with non-ACA. Genetic alterations induced by additional chromosomal changes may be associated with disease progression and poorer overall survival rates in infants with MLL-rearranged ALL.
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http://dx.doi.org/10.1016/j.leukres.2008.03.018DOI Listing
October 2008

NOTCH1 mutation can be an early, prenatal genetic event in T-ALL.

Blood 2008 Jan 27;111(1):376-8. Epub 2007 Sep 27.

Section of Haemato-Oncology, Institute of Cancer Research, London.

NOTCH1 mutations are common in T-lineage acute lymphoblastic leukemia (T-ALL). Twin studies and retrospective screening of neonatal blood spots provide evidence that fusion genes and other chromosomal abnormalities associated with pediatric leukemias can originate prenatally. Whether this is also the case for NOTCH1 mutations is unknown. Eleven cases of T-ALL were screened for NOTCH1 mutations and 4 (36%) had mutations in either the heterodimerization (HD) or proline glutamic acid/serine/threonine (PEST) domains. Of these 4, 3 could be amplified by mutation-specific polymerase chain reaction primers. In one of these 3, with the highest sensitivity, NOTCH1 mutation was detected in neonatal blood spots. In this patient, the blood spot was negative for SIL-TAL1 fusion, present concomitant with NOTCH1 mutation, in the diagnostic sample. We conclude that NOTCH1 can be an early or initiating event in T-ALL arising prenatally, to be complemented by a postnatal SIL-TAL1 fusion.
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http://dx.doi.org/10.1182/blood-2007-02-074690DOI Listing
January 2008

MLL chimeric protein activation renders cells vulnerable to chromosomal damage: an explanation for the very short latency of infant leukemia.

Genes Chromosomes Cancer 2006 Aug;45(8):754-60

Section of Haemato-Oncology, The Institute of Cancer Research, London, UK.

MLL fusion genes are a predominant feature of acute leukemias in infants and in secondary acute myeloid leukemia (AML) associated with prior chemotherapy with topo-II poisons. The former is considered to possibly arise in utero via transplacental chemical exposure. A striking feature of these leukemias is their malignancy and remarkably brief latencies implying the rapid acquisition of any necessary additional mutations. We have suggested that these coupled features might be explained if MLL fusion gene encoded proteins rendered cells more vulnerable to further DNA damage and mutation in the presence of chronic exposure to the agent(s) that induced the MLL fusion itself. We have tested this idea by exploiting a hormone regulated MLL-ENL (MLLT1) activation system and show that MLL-ENL function in normal murine progenitor cells substantially increases the incidence of chromosomal abnormalities in proliferating cells that survive exposure to etoposide VP-16. This phenotype is associated with an altered pattern of cell cycle arrest and/or apoptosis.
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http://dx.doi.org/10.1002/gcc.20338DOI Listing
August 2006

The association of a distinctive allele of NAD(P)H:quinone oxidoreductase with pediatric acute lymphoblastic leukemias with MLL fusion genes in Japan.

Haematologica 2005 Nov;90(11):1511-5

Section of Haemato-Oncology, Institute of Cancer Research, London, UK.

Background And Objectives: The enzyme NAD(P)H:quinone oxidoreductase (NQO1) detoxifies chemicals with quinone rings including benzene metabolites and flavonoids. Previous studies in Caucasian populations have provided evidence that a loss of function allele at nt 609 (C609T, Pro187Ser) is associated with increased risk of infant acute lymphoblastic leukemia (ALL) with MLL-AF4 fusion genes.

Design And Methods: We genotyped 103 infants (<18 months) with ALL or acute myeloid leukemia (AML) in Japan and 185 controls for the frequency of allelic variation at nt 609 and 465 in NQO1 using standardized polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology.

Results: The C609T polymorphism is very common in Japan but we found no link with altered risk for infant ALL. However, a variant of another allele at nt 465 (C465T, Arg139Trp), also associated with diminished enzyme activity, was strongly associated (OR 6.36; CI 1.84-21.90; p=0.002) with infant ALL, especially in t(4;11)(q21;q23), MLL-AF4. No association was found between this allele and risk of infant AML with MLL gene fusions or infant ALL without MLL gene fusions. The same C465T allele has been linked recently, in an Oriental population, to sensitivity to benzene hematotoxicity.

Interpretation And Conclusions: These data endorse the notion that infant ALL with MLL fusion genes have a unique etiology possibly involving transplacental exposure to chemicals.
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November 2005

Molecular pathogenesis of MLL-associated leukemias.

Int J Hematol 2005 Jul;82(1):9-20

Section of Haemato-Oncology, Institute of Cancer Research, London, UK.

Chromosome translocations disrupting the MLL gene are associated with various hematologic malignancies but are particularly common in infant and secondary therapy-related acute leukemias. The normal MLL-encoded protein is an essential component of a supercomplex with chromatin-modulating activity conferred by histone acetylase and methyltransferase activities, and the protein plays a key role in the developmental regulation of gene expression, including Hox gene expression. In leukemia, this function is subverted by breakage, recombination, and the formation of chimeric fusion with one of many alternative partners. Such MLL translocations result in the replacement of the C-terminal functional domains of MLL with those of a fusion partner, yielding a newly formed MLL chimeric protein with an altered function that endows hematopoietic progenitors with self-renewing and leukemogenic activity. This potent impact of the MLL chimera can be attributed to one of 2 kinds of activity of the fusion partner: direct transcriptional transactivation or dimerization/oligomerization. Key unresolved issues currently being addressed include the set of target genes for MLL fusions, the stem cell of origin for the leukemias, the role of additional secondary mutations, and the origins or etiology of the MLL gene fusions themselves. Further elaboration of the biology of MLL gene-associated leukemia should lead to novel and specific therapeutic strategies.
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http://dx.doi.org/10.1532/IJH97.05042DOI Listing
July 2005

Directing oncogenic fusion genes into stem cells via an SCL enhancer.

Proc Natl Acad Sci U S A 2005 Jan 13;102(4):1133-8. Epub 2005 Jan 13.

Section of Haemato-Oncology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, United Kingdom.

TEL-TRKC is a fusion gene generated by chromosomal translocation and encodes an activated tyrosine kinase. Uniquely, it is found in both solid tumors and leukemia. However, a single exon difference (in TEL) in TEL-TRKC fusions is associated with the two sets of cancer phenotypes. We expressed the two TEL-TRKC variants in vivo by using the 3' regulatory element of SCL that is selectively active in a subset of mesodermal cell lineages, including endothelial and hematopoietic stem cells and progenitors. The leukemia form of TEL-TRKC (-exon 5 of TEL) enhanced hematopoietic stem cell renewal and initiated leukemia. In contrast, the TEL-TRKC solid tumor variant (+ TEL exon 5) elicited an embryonic lethal phenotype with impairment of both angiogenesis and hematopoiesis indicative of an effect at the level of the hemangioblasts. The ability of TEL-TRKC to repress expression of Flk1, a critical regulator of early endothelial and hematopoietic cells, depended on TEL exon 5. These data indicate that related oncogenic fusion proteins similarly expressed in a hierarchy of early stem cells can have selective, cell type-specific developmental impacts.
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http://dx.doi.org/10.1073/pnas.0405318102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC545834PMC
January 2005

The small oligomerization domain of gephyrin converts MLL to an oncogene.

Blood 2004 May 29;103(10):3876-82. Epub 2004 Jan 29.

Leukaemia Research Fund Centre, Institute of Cancer Research, Chester Beatty Laboratories, London, United Kingdom.

The MLL (mixed lineage leukemia) gene forms chimeric fusions with a diverse set of partner genes as a consequence of chromosome translocations in leukemia. In several fusion partners, a transcriptional activation domain appears to be essential for conferring leukemogenic capacity on MLL protein. Other fusion partners, however, lack such domains. Here we show that gephyrin (GPHN), a neuronal receptor assembly protein and rare fusion partner of MLL in leukemia, has the capacity as an MLL-GPHN chimera to transform hematopoietic progenitors, despite lack of transcriptional activity. A small 15-amino acid tubulin-binding domain of GPHN is necessary and sufficient for this activity in vitro and in vivo. This domain also confers oligomerization capacity on MLL protein, suggesting that such activity may contribute critically to leukemogenesis. The transduction of MLL-GPHN into hematopoietic progenitor cells caused myeloid and lymphoid lineage leukemias in mice, suggesting that MLL-GPHN can target multipotent progenitor cells. Our results, and other recent data, provide a mechanism for oncogenic conversion of MLL by fusion partners encoding cytoplasmic proteins.
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http://dx.doi.org/10.1182/blood-2003-11-3817DOI Listing
May 2004

The role of the MLL gene in infant leukemia.

Int J Hematol 2003 Dec;78(5):390-401

LRF Centre for Cell and Molecular Biology of Leukaemia, Institute of Cancer Research, London, UK.

The MLL gene is a major player in leukemia, particularly in infant leukemia and in secondary, therapy-related acute leukemia. The normal MLL gene plays a key role in developmental regulation of gene expression (including HOX genes), and in leukemia this function is subverted by breakage, recombination, and chimeric fusion with one of 40 or more alternative partner genes. In infant leukemias, the chromosome translocations involving MLL arise during fetal hematopoiesis, possibly in a primitive lymphomyeloid stem cell. In general, these leukemias have a very poor prognosis. The malignancy of these leukemias is all the more dramatic considering their very short preclinical natural history or latency. These data raise fundamental issues of how such divergent MLL chimeric genes transform cells, why they so rapidly evolve to a malignant status, and what alternative or novel therapeutic strategies might be considered. We review here progress in tackling these questions.
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http://dx.doi.org/10.1007/BF02983811DOI Listing
December 2003