Japan Key Points• We found the defective ALDH2 variant is associated with accelerated progression of BMF in Japanese FA patients.• The data support the view that aldehydes are an important source of genotoxicity in the human hematopoietic system.Fanconi anemia (FA) is a severe hereditary disorder with defective DNA damage response and repair. It is characterized by phenotypes including progressive bone marrow failure (BMF), developmental abnormalities, and increased occurrence of leukemia and cancer. Recent studies in mice have suggested that the FA proteins might counteract aldehydeinduced genotoxicity in hematopoietic stem cells. Nearly half of the Japanese population carries a dominant-negative allele (rs671) of the aldehyde-catalyzing enzyme ALDH2 (acetaldehyde dehydrogenase 2), providing an opportunity to test this hypothesis in humans. We examined 64 Japanese FA patients, and found that the ALDH2 variant is associated with accelerated progression of BMF, while birth weight or the number of physical abnormalities was not affected. Moreover, malformations at some specific anatomic locations were observed more frequently in ALDH2-deficient patients. Our current data indicate that the level of ALDH2 activity impacts pathogenesis in FA, suggesting the possibility of a novel therapeutic approach. (Blood. 2013;122(18):3206-3209) IntroductionFanconi anemia (FA) is a genomic instability disorder with phenotypes including progressive bone marrow failure (BMF), developmental abnormalities, and increased occurrence of leukemia and cancer. 1 To date, 16 genes have been implicated in FA, and their products form a common DNA repair network ("FA pathway"). 2,3Because FA cells are hypersensitive to DNA interstrand crosslinks (ICLs), the FA pathway has been considered to be involved in the repair of ICLs.2,3 However, it remains unclear what type of endogenous DNA damage is repaired through the FA pathway. Recent studies have suggested that FA cells are also sensitive to aldehydes, 4 which may create DNA adducts including ICLs or DNA-protein crosslinks. Furthermore, double knockout mice deficient in Fancd2 and Aldh2, but neither of the single mutant mice, display an accelerated development of leukemia and BMF. 5,6 On the other hand, Fanc-deficient mice in general do not fully recapitulate the human FA phenotype, including overt BMF. Thus, the role of aldehydes in the pathogenesis of human FA is still uncertain.ALDH2 deficiency resulting from a Glu504Lys substitution (rs671, hereinafter referred to as the A allele) is highly prevalent in East Asian populations. The A allele (Lys504) acts as a dominant negative, since the variant form can suppress the activity of the Glu504 form (G allele) in GA heterozygotes by the formation of heterotetramers.8 Individuals with the A variant experience flushing when drinking alcohol, and have an elevated risk of esophageal cancer with habitual drinking.9 Because the frequency of the A allele is close to 50% in the Japanese population at large, some Japanese FA patients are expected to be def...

Summary Reactive aldehydes arise as by-products of metabolism and are normally cleared by multiple families of enzymes. We find that mice lacking two aldehyde detoxifying enzymes, mitochondrial ALDH2 and cytoplasmic ADH5, have greatly shortened lifespans and develop leukemia. Hematopoiesis is disrupted profoundly, with a reduction of hematopoietic stem cells and common lymphoid progenitors causing a severely depleted acquired immune system. We show that formaldehyde is a common substrate of ALDH2 and ADH5 and establish methods to quantify elevated blood formaldehyde and formaldehyde-DNA adducts in tissues. Bone-marrow-derived progenitors actively engage DNA repair but also imprint a formaldehyde-driven mutation signature similar to aging-associated human cancer mutation signatures. Furthermore, we identify analogous genetic defects in children causing a previously uncharacterized inherited bone marrow failure and pre-leukemic syndrome. Endogenous formaldehyde clearance alone is therefore critical for hematopoiesis and in limiting mutagenesis in somatic tissues.

An increasing number of long-term surviving bone marrow transplant (BMT) recipients have recovered from their primary disease but are at risk of developing failure of endocrine organs. We investigated 147 patients who underwent allogeneic BMT. Thyroid function was evaluated by serial measurement of basal TSH and free T4 levels as well as by TRH provocative test. Thyroid ultrasound examination was performed for evaluation of thyroid tumor after BMT. Five patients were found to have overt thyroid dysfunction (hypothyroidism in four patients and hyperthyroidism in one patient). Twenty-three patients in the under 9-yr-old group at BMT and 16 patients in the over 10-yr-old group at BMT had subclinical compensated hypothyroidism. Younger age at BMT was the strongest factor for developing thyroid dysfunction, compared with older age (P < 0.001). Only in patients with subclinical compensated hypothyroidism did median basal and peak TSH increase to the upper half of the normal range by 8 yr after BMT and then returned slightly to the middle of the normal range spontaneously. These results suggest that thyroid dysfunction in long-term BMT survivors depends on age at BMT, with a greater risk among younger patients, indicating the need for life-long surveillance.

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Summary:infections early after BMT 3 and the late complication of vascular damage which may be caused by hypersensitivity to the conditioning agents 4 or interstitial lung disease. 5 Chronic restrictive lung disease in a 9-year-old boy with dyskeratosis congenita (DC) 7 years after allogeneicObstructive lung disease (OLD) has been described as a serious complication after allogeneic BMT. The developbone marrow transplantation (BMT) is described. When he was 1 year and 10 months old, severe aplastic ment of OLD was strongly associated with chronic GVHD. 6 Both clinical and histologic features of DC are very similar anemia developed. He received a marrow transplant from his HLA serologically identical, but HLA-DP misto that of chronic GVHD. 7 Additionally, some cases of DC have been reported to develop chronic pulmonary matched brother. He developed grade II acute graftversus-host disease (GVHD) and thereafter chronic disease. 8,9 We describe a case of DC with chronic restrictive lung disease 7 years after HLA-DP mismatched GVHD of progressive type, and was treated with both prednisolone and azathioprine resulting in clinical allogeneic BMT, and report the results of immunological and histologic examination. improvement. Thereafter he complained of dyspnea, and bilateral noncircumscribed interstitial shadows on chest CT scan were present. His pulmonary function showed restrictive changes. Prednisolone was not effecCase report tive and he died of respiratory failure. Post-mortem examination confirmed interstitial fibrosis, lymphocytic A 1-year and 10 months-old boy was referred to our hospital because of epistaxis. He was the third child of healthy infiltration of the bronchioles and alveoli with luminal fibrosis. There was no evidence of chronic GVHD in the parents, and there was no family history of skin or hematological disorders. He was noted to have reticular pigmenskin and the liver. These findings raise the possibility that this pulmonary complication was associated with tation and progressive nail dystrophy of both fingers and toes. He also had a congenital visual defect of the left eye. DC itself. Keywords: dyskeratosis congenita; allogeneic bone A brain CT scan showed bilateral parieto-occipital calcifications. Leukoplakia of the oral mucous membrane was not marrow transplantation; chronic GVHD; restrictive lung disease observed. Laboratory data revealed a hemoglobin of 5.4 g/dl, white blood cell count of 3.8 × 10 9 /l (absolute neutrophil count of 1.4 × 10 9 /l), and a platelet count of 19 × 10 9 /l. Bone marrow aspiration showed hypoplasia of Dyskeratosis congenita is a rare hereditary disorder characall cell lineages, and the number of hematopoietic progeniterized by reticular hyperpigmentation of the skin, dystor cells was reduced in colony assay. Cytogenetic studies trophy of the nails, and leukoplakia of mucosal memwere normal and there were no chromosomal breaks. branes. 1 It is frequently associated with severe aplastic Because treatment with anabolic steroids and prednisolone anemia and malignant...

Mutations in RAS, neurofibromatosis type 1 (NF1), and PTPN11, constituents of the granulocyte-macrophage colonystimulating factor signaling pathway, have been recognized in patients with juvenile myelomonocytic leukemia (JMML). We assessed 71 children with JMML for NRAS, KRAS, and PTPN11 mutations and evaluated their clinical significance. Of the 71 patients, three had been clinically diagnosed with neurofibromatosis type 1, and PTPN11 and NRAS/KRAS mutations were found in 32 (45%) and 13 (18%) patients, respectively. No simultaneous aberrations were found. Compared with patients with RAS mutation or without any aberrations, patients with PTPN11 mutation were significantly older at diagnosis and had higher fetal Hb levels, both of which have been recognized as poor prognostic factors. As was expected, overall survival was lower for patients with the PTPN11 mutation than for those without (25 versus 64%; p ϭ 0.0029). In an analysis of 48 patients who received hematopoietic stem cell transplantation, PTPN11 mutations were also associated with poor prognosis for survival. Mutation in PTPN11 was the only unfavorable factor for relapse after hematopoietic stem cell transplantation (p ϭ 0.001). All patients who died after relapse had PTPN11 mutation. These results suggest that JMML with PTPN11 mutation might be a distinct subgroup with specific clinical characteristics and poor outcome.

Our approach utilizing targeted sequencing and WES achieved satisfactory diagnostic rates and supported the efficacy of massive parallel sequencing as a diagnostic tool for IBMFS.Genet Med advance online publication 19 January 2017.

Summary:To establish the most appropriate prophylactic therapy and risk factors for predicting hemorrhagic cystitis (HC) after stem cell transplantation (SCT), we retrospectively analyzed the clinical records of 450 transplant patients treated from 1982 to 2002. In all, 81 patients developed early-and/or late-onset HC (early ¼ 29, late ¼ 48, both ¼ 4). For the incidence of early-onset HC, administration of cyclophosphamide (CY) (P ¼ 0.0079, odds ratioCI ¼ 2.055-9.292), antithymocyte globulin (P ¼ 0.0009, OD ¼ 3.368, 95% CI ¼ 1.642-6.911), nonradiation (P ¼ 0.0163, OD ¼ 2.564, 95% CI ¼ 0.181-0.841), 2-mercaptoethane sodium sulfonate (Mesna) (P ¼ 0.0001, OD ¼ 7.519, 95% CI ¼ 2.847-19.858), and bladder irrigation (P ¼ 0.0001, OD ¼ 4.950, 95% CI ¼ 2.328-10.523) were risk factors. By Fisher's exact test, the combination of BU and Mesna was a more significant risk factor (Po0.001) than Mesna alone (P ¼ 0.008) compared to the administration of neither agent. By multivariate analysis, prophylactic administration of Mesna (P ¼ 0.0105, OD ¼ 5.301, 95% CI ¼ 1. 477-19.026) and bladder irrigation (P ¼ 0.0001, OD ¼ 9.469, 95% CI ¼ 3.872-23.156) were significant risk factors of early-onset HC. We conclude that (i) highdose BU as well as CY is a cause of HC, (ii) protective bladder irrigation has an opposite effect, and (iii) Mesna possibly has a toxic effect on bladder mucosa. Bone Marrow Transplantation (2003) 32, 903-907.