Takuya Kamio

Correction of immunodeficiency associated with NEMO mutation by umbilical cord blood transplantation using a reduced-intensity conditioning regimen

Correction of immunodeficiency associated with NEMO mutation by umbilical cord blood transplantation using a reduced-intensity conditioning regimen

Relapse of aplastic anemia in children after immunosuppressive therapy: a report from the Japan Childhood Aplastic Anemia Study Group

Background Although the therapeutic outcome of acquired aplastic anemia has improved markedly with the introduction of immunosuppressive therapy using antithymocyte globulin and cyclosporine, a significant proportion of patients subsequently relapse and require second-line therapy. However, detailed analyses of relapses in aplastic anemia children are limited. Design and Methods We previously conducted two prospective multicenter trials of immunosuppressive therapy for children with aplastic anemia: AA-92 and AA-97, which began in 1992 and 1997, respectively. In this study, we assessed the relapse rate, risk factors for relapse, and the response to second-line treatment in children with aplastic anemia treated with antithymocyte globulin and cyclosporine. Results From 1992 to 2007, we treated 441 children with aplastic anemia with standard immunosuppressive therapy. Among the 264 patients who responded to immunosuppressive therapy, 42 (15.9%) relapsed. The cumulative incidence of relapse was 11.9% at 10 years. Multivariate analysis revealed that relapse risk was significantly associated with an immunosuppressive therapy regimen using danazol (relative risk, 3.15; P=0.001) and non-severe aplastic anemia (relative risk, 2.51; P=0.02). Seventeen relapsed patients received additional immunosuppressive therapy with antithymocyte globulin and cyclosporine. Eight patients responded within 6 months. Seven of nine non-responders to second immunosuppressive therapy received hematopoietic stem cell transplantation and five are alive. Eleven patients underwent hematopoietic stem cell transplantation directly and seven are alive. Conclusions In the present study, the cumulative incidence of relapse at 10 years was relatively low compared to that in other studies mainly involving adult patients. A multicenter prospective study is warranted to establish optimal therapy for children with aplastic anemia.

Two novel variants of MOZ-CBP fusion transcripts in spontaneously remitted infant leukemia with t(1;16;8)(p13;p13;p11), a new variant of t(8;16)(p11;p13)

Translocation t(8;16)(p11;p13) involving the MOZ/MYST3 gene (8p11) and the CBP/CREBBP gene (16p13) is associated with the FAB M4/M5 subtype of acute myeloid leukemia (AML) and a poor prognosis. Five types of MOZ-CBP and three types of CBP-MOZ fusion transcripts have been identified in adult and

Voriconazole for both successful treatment of disseminated Trichosporon asahii infection and subsequent cord blood transplantation in an infant with acute myelogenous leukemia

Voriconazole for both successful treatment of disseminated Trichosporon asahii infection and subsequent cord blood transplantation in an infant with acute myelogenous leukemia

Exome sequencing identified RPS15A as a novel causative gene for Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome, characterized by red blood cell aplasia, macrocytic anemia, variable malformations, and increased risk of malignancy.[1][1]–[3][2] DBA has been associated with heterozygous mutations or large deletions in ribosomal protein

Gene alterations involving the CRLF2-JAK pathway and recurrent gene deletions in Down syndrome-associated acute lymphoblastic leukemia in Japan

In Western countries, gene alterations involving the CRLF2‐JAK signaling pathway are identified in approximately 50–60% of patients with Down syndrome‐associated acute lymphoblastic leukemia (DS‐ALL), and this pathway is considered a potential therapeutic target. The frequency of BTG1 deletions in DS‐ALL is controversial. IKZF1 deletions, found in 20–30% of DS‐ALL patients, are associated with a poor outcome and EBF1 deletions are very rare (∼2%). We analyzed 38 patients to determine the frequencies and clinical implications of CRLF2‐JAK pathway genetic alterations and recurrent gene deletions in Japanese DS‐ALL patients. We confirmed a high incidence of P2RY8‐CRLF2 (29%) and JAK2 mutations (16%), though the frequency of P2RY8‐CRLF2 was slightly lower than that in Western countries (∼50%). BTG1 deletions were common in our cohort (25%). IKZF1 deletions were detected in 25% of patients and associated with shorter overall survival (OS). EBF1 deletions were found at an unexpectedly high frequency (16%), and at a significantly higher level in P2RY8‐CRLF2‐positive patients than in P2RY8‐CRLF2‐negative patients (44% vs. 4%, P = 0.015). Deletions of CDKN2A/B and PAX5 were common in P2RY8‐CRLF2‐negative patients (48 and 39%, respectively) but not in P2RY8‐CRLF2‐positive patients (11% each). Associations between these genetic alterations and clinical characteristics were not observed except for inferior OS in patients with IKZF1 deletions. These results suggest that differences exist between the genetic profiles of DS‐ALL patients in Japan and in Western countries, and that P2RY8‐CRLF2 and EBF1 deletions may cooperate in leukemogenesis in a subset of Japanese DS‐ALL patients.

Guillain-Barré syndrome mimicking acute methotrexate-associated encephalopathy in an adolescent patient with lymphoblastic lymphoma.

We describe an adolescent case of Guillain-Barré syndrome (GBS) mimicking acute methotrexate-associated encephalopathy during chemotherapy for lymphoblastic lymphoma. Although initial presentations of hemiparesis and irritability were suggestive of acute encephalopathy, the diminished deep tendon reflexes and subsequent rapid progression to flaccid triparesis with bulbar palsy were consistent with GBS. After the initiation of intravenous immunoglobulin therapy her symptoms improved rapidly, and the diagnosis of GBS was confirmed by nerve conduction studies and cerebrospinal fluid examination in recovery phase. GBS should be considered in the differential diagnosis of acute methotrexate-associated encephalopathy, although GBS is a rare neurologic complication.

CD7-positive acute myelomonocytic leukemia with trisomy 21 as a sole acquired chromosomal abnormality in two adolescents

Trisomy 21 is one of the most common acquired chromosomal bnormalities in myeloid malignancies, but is rarely found as a sole nomaly. It has been reported that only 0.3% of adult patients with cute myeloblastic leukemia (AML) or myelodysplastic syndrome ave trisomy 21 as a sole acquired abnormality [1]. Although sevral reports indicate that this karyotypic abnormality is associated ith the French–American–British (FAB) AML subtypes M2, M4 and 5 [2,3] and with a poor prognosis [3,4], its clinical and prognosic implications have not been fully evaluated. Some investigators ave focused on the association between this chromosomal abnorality and CD7 expression, and 4 adult patients with CD7-positive ML have been reported so far [5–8]. Although one report includes adolescent AML cases with trisomy 21 as a sole acquired abnorality [3], there have been no reports on pediatric CD7-positive ML patients with this anomaly. Here, we report 2 unique adolesent cases of CD7-positive acute myelomonocytic leukemia with risomy 21 as a minor clone and as a sole acquired chromosomal bnormality.

Two siblings with familial neuroblastoma with distinct clinical phenotypes harboring an ALK germline mutation

The authors report two siblings with familial neuroblastoma with a germline R1275Q mutation of the tyrosine kinase domain of ALK. Whole exome sequencing and copy number variation assay were performed to investigate genetic alterations in the two cases. No common somatic mutations or gene polymorphisms related to the tumorigenesis of neuroblastoma were detected. A distinct pattern involving both segmental chromosomal alteration and MYCN amplification was detected. The diversity of biological behavior of familial neuroblastoma harboring a germline ALK mutation may depend on conventional prognostic factors, such as segmental chromosomal alterations and MYCN amplification, rather than additional acquired mutations.

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

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