[Show abstract][Hide abstract] ABSTRACT: GATA1 mutations are found almost exclusively in children with myeloid proliferations related to Down syndrome (DS). Here, we report two phenotypically and cytogenetically normal children with acute megakaryoblastic leukemia (AMKL) whose blasts had both acquired trisomy 21 and GATA1 mutation. Patient 1 was diagnosed with transient abnormal myelopoiesis in the neonatal period. Following spontaneous improvement of the disease, leukemic blasts increased 7 months later. He received less intensive chemotherapy, and he is now 6 years old in complete remission. Patient 2 was diagnosed with AMKL at the age of 18 months. Although he received intensive chemotherapy and a cord blood transplantation, he died without gaining remission. In both cases, trisomy 21 and GATA1 mutation were detected only in leukemic blasts, but not in germline samples. Based on a literature review, we identified reports describing 14 non-DS AMKL with GATA1 mutation and acquired trisomy 21. Of those, 12 cases were diagnosed during the neonatal period, whereas the remaining 2 cases were diagnosed at the age of 22 and 31 months, respectively. Conclusion: These cases suggest that GATA1 mutation may cooperate with the additional chromosome 21 in developing myeloid proliferations even in non-DS patients.
European Journal of Pediatrics 09/2014; · 1.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IPEX syndrome is a rare and fatal disorder caused by absence of regulatory T cells (Tregs) due to congenital mutations in the Forkhead box protein 3 gene. Here, we report a patient with IPEX syndrome treated with RIC followed by allogeneic BMT from an HLA-matched sibling donor. We could achieve engraftment and regimen-related toxicity was well tolerated. Although the patient was in mixed chimera and the ratio of donor cells in whole peripheral blood remained relatively low, selective and sustained expansion of Tregs determined as CD4+CD25+Foxp3+ cells was observed. Improvement in clinical symptoms was correlated with expansion of donor-derived Tregs and disappearance of anti-villin autoantibody, which was involved in the pathogenesis of gastrointestinal symptoms in IPEX syndrome. This clinical observation suggests that donor-derived Tregs have selective growth advantage in patients with IPEX syndrome even in mixed chimera after allogeneic BMT and contribute to the control of clinical symptoms caused by the defect of Tregs.
[Show abstract][Hide abstract] ABSTRACT: Infants (<1 year old) with acute myeloid leukemia (AML) are particularly vulnerable to intensive cytotoxic therapy. Indeed, the mortality rate was high among infants enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study, which prompted us to temporarily suspend patient enrollment and amend the protocol. Forty-five infants with AML were enrolled. For patients aged <2 years, drug doses were adjusted for body weight. Following the protocol amendments, doses for infants were reduced by a further 33 % in the initial induction course. Six infants died during the induction phase (including five early deaths), mainly due to pulmonary complications. The 3-year probability of overall survival (pOS) in all 45 infants [55.9 %, 95 % confidence interval (CI) 37.9-70.6 %] was significantly lower than that of patients aged 1 to <2 years (77.0 %, 95 % CI 62.7-86.3 %) and those aged ≥2 years (74.7 %, 95 % CI 69.2-79.4 %) (P = 0.037), mainly due to the higher non-relapse mortality rate in infants. No early deaths occurred after the protocol amendments, and the 3-year pOS of the 17 infants enrolled thereafter was 76.4 % (95 % CI 48.8-90.4 %). In conclusion, appropriate dose reduction is essential to avoid early deaths when treating infants with AML.
International journal of hematology 09/2013; · 1.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Transient abnormal myelopoiesis (TAM) is a myeloid proliferation resembling acute megakaryoblastic leukemia (AMKL), mostly affecting perinatal infants with Down syndrome. Although self-limiting in a majority of cases, TAM may evolve as non-self-limiting AMKL after spontaneous remission (DS-AMKL). Pathogenesis of these Down syndrome-related myeloid disorders is poorly understood, except for GATA1 mutations found in most cases. Here we report genomic profiling of 41 TAM, 49 DS-AMKL and 19 non-DS-AMKL samples, including whole-genome and/or whole-exome sequencing of 15 TAM and 14 DS-AMKL samples. TAM appears to be caused by a single GATA1 mutation and constitutive trisomy 21. Subsequent AMKL evolves from a pre-existing TAM clone through the acquisition of additional mutations, with major mutational targets including multiple cohesin components (53%), CTCF (20%), and EZH2, KANSL1 and other epigenetic regulators (45%), as well as common signaling pathways, such as the JAK family kinases, MPL, SH2B3 (LNK) and multiple RAS pathway genes (47%).
[Show abstract][Hide abstract] ABSTRACT: Optic pathway oligodendrogliomas are a rare form of pediatric intracranial tumor. A 10-year-old girl presented with symptoms of hydrocephalus and seizure. Head computed tomography and magnetic resonance images showed hydrocephalus, chiasmal tumor, and enlarged and tortuous optic nerves. The tumor was partially removed by operation and diagnosed as oligodendroglioma. Operatively, there was evidence of cerebrospinal fluid dissemination in the sylvian fissure indicating widespread invasion. After the operation, Packer's regimen (vincristine and carboplatin therapy) was administered. However, magnetic resonance images obtained 2 months after the operation revealed enlargement of the original tumor and the appearance of new lesions, and treatment was changed to irradiation and temozolomide therapy according to the presence of a high-grade glioma. Two years after the operation, the patient is free of neurological symptoms, and the tumor is controlled with partial response. This is the first report of pediatric optic pathway oligodendroglioma presenting widespread invasion and cerebrospinal dissemination.
[Show abstract][Hide abstract] ABSTRACT: In pediatric acute myeloid leukemia (AML), cytogenetic abnormalities are strong indicators of prognosis. Some recurrent cytogenetic abnormalities, such as t(8;16)(p11;p13), are so rare that collaborative studies are required to define their prognostic impact. We collected the clinical characteristics, morphology and immunophenotypes of 62 pediatric AML patients with t(8;16)(p11;p13) from 18 countries participating in the I-BFM AML study group. We used the AML-BFM cohort diagnosed from 1995-2005 (n = 543) as a reference cohort. Median age of the pediatric t(8;16)(p11;p13) AML patients was significantly lower (1.2 years). The majority (97%) had M4-M5 FAB type, significantly different from the reference cohort. Erythrophagocytosis (70%), leukemia cutis (58%) and disseminated intravascular coagulation (39%) occurred frequently. Strikingly, spontaneous remissions occurred in 7 neonates with t(8;16)(p11;p13), of whom 3 remain in continuous remission. The 5-year overall survival of patients diagnosed after 1993 was 59%, similar to the reference cohort(p=0.14). Gene expression profiles of t(8;16)(p11;p13) pediatric AML cases clustered close to, but distinct from, MLL-rearranged AML. Highly expressed genes included HOXA11, HOXA10, RET, PERP and GGA2. In conclusion, pediatric t(8;16)(p11;p13) AML is a rare entity defined by a unique gene expression signature and distinct clinical features in whom spontaneous remissions occur in a subset of neonatal cases.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: Treatment strategy of malignant congenital brain tumor is controversial. We report a congenital embryonal tumor case with various pathological components. METHODS: A normally delivered male infant had an enlarged head circumference at 1 month after birth. The abnormality of the right side of the head was also noted during the routine 4-month health check. The head circumference was 45.1 cm (+2.25, SD); neurological status, however, was normal, with a pediatric GCS of 9 and body weight of 6,370 g (-0.85, SD). Magnetic resonance imaging (MRI) revealed right brain tumor whose size was 99 × 91 × 86 mm. The tumor was enhanced homogeneously with central necrosis, and the margin of the tumor was well circumscribed. RESULTS: We performed a subtotal removal of the tumor. The pathological diagnosis was meningioma (MIB-1 index was 2 %). The residual tumor gradually shrank, and we performed monthly MRI follow-up. The tumor abruptly recurred 7 months after the operation. The level of patient consciousness deteriorated, and emergency removal surgery was performed. The histological examination showed various types of embryonal components without meningioma-like parts. The pathological diagnosis was an embryonal tumor. The MIB-1 index was 48 %. One month after the second operation, dissemination of the tumor occurred at the right temporal lobe, cerebellum, and in subcutaneous tissue. Chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide) was initiated following radiation therapy (3 Gy/day, 8×). Adjuvant therapies were effective, and no tumor recurrence was detected during 34 months follow-up. CONCLUSION: Treatment strategies for malignant indefinite diagnosed tumor need to be discussed.
Child s Nervous System 06/2013; 29(6):921-926. · 1.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Key points Genetically heterogeneous subclones with varying leukemia-initiating potential exist in neonatal transient abnormal myelopoiesisThis novel xenograft model of transient abnormal myelopoiesis may provide unique insight into the evolutionary process of leukemia.
[Show abstract][Hide abstract] ABSTRACT: Down syndrome (DS) children have an increased incidence of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia (AMKL). The majority of these cases harbor somatic mutations in the GATA1 gene, which results in the loss of full-length of GATA1, accordingly only a truncated isoform of GATA1 that lacks the N-terminal 83 amino acids (GATA1-S) remains. We found through genetic studies in 106 TAM patients that internally deleted GATA1 proteins (GATA1-IDs) lacking amino acid residues 77-119 or 74-88 (created by splicing mutations) contributed to the genesis of TAM in six patients. Analyses of GATA1-deficient embryonic megakaryocytic progenitors revealed that the GATA1 function in growth restriction was disrupted in GATA1-IDs. In contrast, GATA1-S rather promoted megakaryocyte proliferation more profoundly than that induced by GATA1-deficiency. These results indicate that the internally deleted regions play important roles in megakaryocyte proliferation and perturbation of this mechanism is involved in the pathogenesis of TAM.
[Show abstract][Hide abstract] ABSTRACT: The acute myeloid leukaemia (AML) 99 trial conducted previously in Japan for the treatment of de novo paediatric AML showed excellent results, with a 5-year overall survival (OS) and event-free survival (EFS) of 75·6% and 61·6%, respectively. To examine reproducibility of these results in another cohort, the outcome of 146 newly diagnosed AML paediatric patients prospectively registered in the Japan Association of Childhood Leukaemia Study (JACLS) from 2003 to 2006 was compared to that of 240 patients in the original AML 99 clinical trial. The 5-year EFS and OS achieved in the new cohort was 66·7 ± 4·0% and 77·7 ± 8·0% respectively, which were comparable to those obtained in the original AML 99 clinical trial, although less frequent core-binding factor (CBF) AML (29·5% vs. 37%) and an almost equal frequency of allogeneic haematopoietic stem cell transplantation (allo-HSCT) during first complete remission (16·5% vs. 19%) were observed. The 5-year EFS in patients with a normal karyotype (NK) (n = 35, 54·9 ± 15·1%) was inferior in the present cohort when compared to the original AML99 trial. This study confirmed the excellent outcome of the original AML99 protocol.
British Journal of Haematology 08/2012; 159(2):204-10. · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Myeloid leukemia in Down syndrome (ML-DS) is associated with good response to chemotherapy and favorable prognosis. Because little research has been focused on refractory/relapsed (R/R) cases, we conducted a retrospective analysis for R/R ML-DS. Among ML-DS patients diagnosed between 2000 and 2010 in Japan, 26 relapsed (25 in the BM and 1 in the skin), and 3 refractory patients were enrolled. The male/female ratio was 18/11. The median age at initial diagnosis of ML-DS was 2 years, and the median time to relapse was 8.6 months. Each patient initially had been treated with ML-DS-specific protocols. Thirteen of the 26 patients achieved complete remission with various kinds of reinduction chemotherapies; 2 of 8 survived without further recurrence after receiving allogeneic hematopoietic stem cell transplantation, and 4 of 5 maintained complete remissions with chemotherapy alone. Treatment failures mostly were associated with disease progression rather than treatment-related toxicities. The 3-year OS rate was 25.9% ± 8.5%. A longer duration from initial diagnosis to relapse was a significant favorable prognostic factor (P < .0001). We conclude that clinical outcome for patients with R/R ML-DS generally are unfavorable, even in those receiving hematopoietic stem cell transplantation. Novel methods to identify poor prognostic factors for ML-DS are necessary.
[Show abstract][Hide abstract] ABSTRACT: X-linked lymphoproliferative syndrome (XLP) type 1 is a rare immunodeficiency, which is caused by mutations in SH2D1A gene. The prognosis of XLP is very poor, and hematopoietic stem cell transplantation (HSCT) is the only curative therapy. We characterized the clinical features and outcome of Japanese patients with XLP-1.
We used a combination of flow cytometric analysis and genetic analysis to identify XLP-1 and reviewed the patient characteristics and survival with HSCT.
We identified 33 patients from 21 families with XLP-1 in Japan. Twenty-one of the patients (65%) who did not undergo a transplant died of the disease and complications. Twelve patients underwent HSCT, and 11 of these (92%) survived.
We described the clinical characteristics and outcomes of Japanese patients with XLP-1, and HSCT was the only curative therapy for XLP-1. The rapid and accurate diagnosis of XLP with the combination of flow cytometric assay and genetic analysis is important.
Pediatric Allergy and Immunology 03/2012; 23(5):488-93. · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fifty percent of Diamond-Blackfan anemia (DBA) patients possess mutations in genes coding for ribosomal proteins (RPs). To identify new mutations, we investigated large deletions in the RP genes RPL5, RPL11, RPL35A, RPS7, RPS10, RPS17, RPS19, RPS24, and RPS26. We developed an easy method based on quantitative-PCR in which the threshold cycle correlates to gene copy number. Using this approach, we were able to diagnose 7 of 27 Japanese patients (25.9%) possessing mutations that were not detected by sequencing. Among these large deletions, similar results were obtained with 6 of 7 patients screened with a single nucleotide polymorphism array. We found an extensive intragenic deletion in RPS19, including exons 1-3. We also found 1 proband with an RPL5 deletion, 1 patient with an RPL35A deletion, 3 with RPS17 deletions, and 1 with an RPS19 deletion. In particular, the large deletions in the RPL5 and RPS17 alleles are novel. All patients with a large deletion had a growth retardation phenotype. Our data suggest that large deletions in RP genes comprise a sizable fraction of DBA patients in Japan. In addition, our novel approach may become a useful tool for screening gene copy numbers of known DBA genes.
[Show abstract][Hide abstract] ABSTRACT: X-linked lymphoproliferative syndrome (XLP) is a rare immunodeficiency with extreme vulnerability to Epstein-Barr virus (EBV) infection. It presents with fatal infectious mononucleosis, lymphoproliferative disorder, or dysgammaglobulinemia. The majority of affected males have mutations in the SH2D1A/SLAM-associated protein (SAP) gene. We previously generated an antihuman SAP monoclonal antibody (KST-3) for a flow cytometric assay and described the activation of T cells to be necessary for the flow cytometric assessment of the SAP expression using an FITC-conjugated secondary antibody.
Between 2005 and 2008, we recruited 23 male patients with suspected XLP, including mainly EBV-associated hemophagocytic lymphohistiocytosis (HLH), and attempted to evaluate SAP expression in fresh lymphoid cells using Alexa Fluor 488-conjugated secondary antibody instead of an FITC-conjugated one.
The method demonstrated that SAP was intensely expressed in CD8(+) T cells and NK cells in normal fresh blood samples, thus suggesting the possible rapid identification of individuals with SAP deficiency. SH2D1A mutations were identified in six patients with SAP deficiency, but not in patients with normal SAP expression.
The outcomes from this trial were verified by a flow cytometric assay using KST-3 and Alexa Fluor 488 secondary antibody. Based on the demonstration SAP deficiency in patients with suspected XLP, including mainly EBV-associated HLH, this approach could serve as a method for the early and rapid detection of patients with XLP-1.
Cytometry Part B Clinical Cytometry 01/2011; 80(1):8-13. · 2.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Twenty percent to 30% of transient abnormal myelopoiesis (TAM) observed in newborns with Down syndrome (DS) develop myeloid leukemia of DS (ML-DS). Most cases of TAM carry somatic GATA1 mutations resulting in the exclusive expression of a truncated protein (GATA1s). However, there are no reports on the expression levels of GATA1s in TAM blasts, and the risk factors for the progression to ML-DS are unidentified. To test whether the spectrum of transcripts derived from the mutant GATA1 genes affects the expression levels, we classified the mutations according to the types of transcripts, and investigated the modalities of expression by in vitro transfection experiments using GATA1 expression constructs harboring mutations. We show here that the mutations affected the amount of mutant protein. Based on our estimates of GATA1s protein expression, the mutations were classified into GATA1s high and low groups. Phenotypic analyses of 66 TAM patients with GATA1 mutations revealed that GATA1s low mutations were significantly associated with a risk of progression to ML-DS (P < .001) and lower white blood cell counts (P = .004). Our study indicates that quantitative differences in mutant protein levels have significant effects on the phenotype of TAM and warrants further investigation in a prospective study.