To evaluate the efficacy of long-term prophylaxis with ultra-low-dose acyclovir against varicella-zoster virus (VZV) reactivation, we analyzed the records of 242 Japanese adult patients who underwent allogeneic hematopoietic stem cell transplantation for the first time from 1995 to 2006 at our hospital. We started long-term oral acyclovir at 200 mg/day in July 2001. Acyclovir was continued until the end of immunosuppressive therapy and at least 1 year after transplantation. Sixty-six patients developed VZV reactivation at a median of 248 days after HSCT, with a cumulative incidence of 34.7%. Only one breakthrough reactivation occurred during long-term acyclovir, which responded well to therapeutic dose of valacyclovir. The use of long-term acyclovir was the only independent determinant that significantly decreased the overall incidence of VZV reactivation (20% vs. 50%, P < 0.0001). With this prophylaxis, visceral dissemination and serious complications other than post-herpetic neuralgia was completely eliminated, and thereby need for hospitalization was significantly reduced (21% vs. 71%, P 5 0.0034). Fifteen of the 57 patients who discontinued acyclovir developed VZV reactivation, with a cumulative incidence of 32.1%. VZV reactivation following discontinuation tended to occur in patients who were receiving immunosuppressive therapy at the cessation of acyclovir. These findings suggested that long-term prophylaxis of ultra-low-dose acyclovir resulted in a successful prevention of severe VZV-related symptoms and death, with a significantly decreased overall incidence of VZV reactivation. Prolongation of prophylactic acyclovir on profound immunosuppression might be important for thorough suppression of VZV reactivation. Am. J. Hematol. 83:472-476, 2008. V

Currently, we utilize vitamins and trace elements formulations that are not prepared specifically for patients receiving hematopoietic stem cell transplantation (HSCT), and adequacy of this strategy has not been evaluated. We prospectively measured blood level of vitamins and trace elements in 15 patients once per week at 6 time points around the acute phase of allogeneic HSCT. We provided standard nutrition support, including administration of parenteral nutrition with vitamin and trace elements formulation in case of impairment of oral intake. Most patients had vitamin B1 deficiency from the start of preparative regimens. Vitamin C deficiency was prominent throughout the acute phase of HSCT and this was significantly associated with high inflammatory markers, C-reactive protein and ferritin. Remarkable vitamin K overload associated with administration of parenteral supplementation and ferritin overload caused by repeated transfusions was observed. Moderate deficiency of zinc was at least partially linked to gastrointestinal loss by diarrhea. We revealed several features of vitamin and trace element status in the acute phase of HSCT and provided a basis for attempts to improve the nutritional condition in HSCT recipients.

IntroductionFunctional disruption of tumor-suppressive transcription factors, such as p53, has been widely found in many types of tumors. Although great efforts have been made to reactivate wild-type p53, 1 therapeutic interventions to impaired transcription factors still need innovative strategy. To overcome this difficulty, we need to seek the treatable and pathogenetic targets for deregulated transcription factors.Transcription factor AML1, also known as RUNX1, is one of the most frequent targets of chromosomal abnormalities in human leukemia. 2 Functional impairment of AML1 caused by point mutation also is reported in patients with leukemia or myelodysplastic syndrome (MDS). [3][4][5][6] Patients who have AML1 mutations are reported to be accompanied with poor prognosis. 5,6 Genetic disruptions of AML1 also are known to cause familial platelet disorder, with predisposition to acute myelogenous leukemia (AML). 7 AML1 is a critical regulator in hematopoiesis and has an essential function in the establishment of definitive hematopoiesis, differentiation of lymphocytes, maturation of megakaryocytes, and regulation of hematopoietic stem cells (HSCs). [8][9][10][11] Point mutations of AML1 have been found throughout the length of this gene in myeloid tumors such as AML or MDS; most of the mutants loose the potential to activate gene transcription, whereas some mutants show a dominant-negative effect over AML1 function. 4,12 The types of mutations are similar between AML and MDS. Significantly, it was recently reported that AML1 mutants cause MDS/AML in a mouse bone marrow transplantation (BMT) model. 13 To date, many target genes of AML1 have been reported. 14,15 However, the signaling pathways involved in the pathogenesis of AML1-related leukemia are still elusive.t(8;21) produces the chimeric protein AML1/ETO and is one of the most frequent chromosomal translocations found in AML. AML1/ETO is constituted of the N-terminal AML1-derived part and the C-terminal ETO part that contain a DNA-binding domain and a corepressor-binding domain, respectively. Besides the defect of trans-activation potential, AML1/ETO is a potent repressor of gene transcription and acts as a dominant-negative mutant of AML1.Nuclear factor-B is a dimeric complex of transcription factors mainly consisting of p65 (RelA)/p50 (NFKB1) or RelB/p52 (NFKB2). There are 2 major pathways in NF-B signaling: the canonical pathway that broadly modulates cell proliferation, survival, or inflammation; and the noncanonical pathway that mainly controls lymphogenesis or B-cell maturation. 16 In the canonical pathway, p65 and p50 (NFKB1) constitute NF-B complex and are localized in the cytoplasm with IB in a steady state. Once inflammation is induced, TNF-␣ stimulates its receptor that in turn activates the IB kinase (IKK) complex. Then, IB is phosphorylated by the activated IKK complex and subsequently degraded through the ubiquitinproteasome pathway, resulting in nuclear translocation of p65/ p50 and transactivation of NF-B target genes. In the noncanonical pa...

Total body irradiation (TBI) has been thought to promote donor cell engraftment in allogeneic hematopoietic cell transplantation (HCT) from alternative donors. However, recent progress in HCT strategies may affect the clinical significance of TBI on neutrophil engraftment. With the use of a Japanese transplant registry database, we analyzed 3933 adult recipients (>15 y.o.) who underwent HCT between 2006 and 2013 from an 8/8 HLA-matched unrelated bone marrow donor (MUD, n = 1367), an HLA-mismatched unrelated bone marrow donor (MMUD, n = 1102), or unrelated cord blood (CBT, n = 1464). Conditioning regimens were divided into five groups: High-TBI-(>8Gy), Low-TBI- (≤8Gy), and no-TBI-myeloablative conditioning (MAC), and Low-TBI- and no-TBI-reduced-intensity conditioning (RIC). In both MUD and MMUD, neutrophil engraftment rate was >90% in each of the five conditioning groups, and TBI was not associated with prompt neutrophil engraftment in multivariate analyses. Conversely, in CBT, TBI regimens had a higher rate of day-30 neutrophil engraftment than no-TBI-regimens: 78% in High-TBI-MAC, 83% in Low-TBI-MAC, and 76% in Low-TBI-RIC versus 65% in No-TBI-MAC, and 68% in No-TBI-RIC (P < .001). Multivariate analyses in CBT demonstrated that TBI-regimens were significantly associated with a higher rate of neutrophil engraftment. Subsequently focusing on CBT patients alone, TBI-regimens were significantly associated with a higher rate of neutrophil engraftment in patients who received CBT with a 4/6 or less HLA allele-match, or who had anti-HLA antibodies. In summary, TBI-regimens had no impact on neutrophil engraftment in the current practice of unrelated bone marrow transplantation. However, in CBT, TBI is still necessary to enhance engraftment.

GM antigen results must be considered cautiously in conjunction with other diagnostic procedures including computed tomography scans, especially during the first 100 days after HSCT and in patients with gastrointestinal chronic GVHD.

Late cytomegalovirus (CMV) disease beyond day 100 after hematopoietic stem cell transplantation (HSCT) has become an increasing problem after the introduction of preemptive ganciclovir (GCV) administration. To clarify the risk factors and outcome for late CMV reactivation and disease, we retrospectively analyzed the records of 101 Japanese adult patients who underwent allogeneic HSCT between 1998 and 2005 at our hospital. Fifty-one developed late positive CMV antigenemia, with a cumulative incidence of 53%. Recipient CMV seropositivity, the use of alemtuzumab, chronic GVHD, and high-dose steroids were significantly associated with late positive antigenemia. Eight patients developed late CMV disease, with a cumulative incidence of 8%, including retinitis and gastrointestinal disease. None progressed to a fatal disease. The use of alemtuzumab was identified as an independent significant risk factor for late CMV disease, although it was not associated with increased non-relapse mortality. Among the 51 patients with late positive antigenemia, 28 had consistently less than three positive cells, 25 of whom showed negative conversion without antiviral agents. In conclusion, late CMV antigenemia appeared to develop frequently, especially in patients with profound immune suppression; however, a fatal outcome could be prevented by optimal preemptive therapy. Low-level antigenemia may not require antiviral treatments.

While most studies regarding reactive oxygen species (ROS) focus on their deleterious biological effects, a growing body of evidence indicates the importance of ROS as critical mediators of several signaling pathways, including those involved in hematopoiesis. In this study, we show the critical role of ROS in lineage decision of myeloid progenitors. In megakaryocyte-erythrocyte progenitor cells (MEP), intracellular ROS levels were found to be as low as those in hematopoietic stem cells (HSC). In contrast, remarkably high intracellular ROS levels were observed in granulocyte-monocyte progenitor cells. Intracellular ROS levels in common myeloid progenitors (CMP) were inversely correlated with their MEP differentiation potential. Moreover, gene set enrichment analysis revealed that ROS-low CMP showed gene expression patterns similar to those of MEP, indicating that intracellular ROS levels mark the fate of CMP. In in vitro assays, ROS significantly suppressed the generation of MEP and the formation of megakaryocyte-erythrocyte colonies from CMP. In ROS-high CMP, expression of colony-stimulating factor one receptor (CSF1R) was highly upregulated, and its surface expression correlated with their granulocyte-monocyte differentiation potential. Furthermore, ROS was found to induce the expression of CSF1R mRNA in a leukemia cell line. These data provide novel insights into the relationship between ROS and the hematopoietic differentiation system. STEM CELLS 2014;32:548-557

Familial platelet disorder (FPD) is a rare autosomal dominant disorder which causes moderate thrombocytopenia with or without impaired platelet function. Patients have a propensity to develop acute myeloid leukemia (AML), and various types of second hits have been postulated in the evolution to AML. However, only a few cases of acute lymphoblastic leukemia (ALL) have been reported thus far. Here, we report a family of FPD with a germ-line hemi-allelic mutation R174X in the RUNX1 gene. The proband of the family developed AML and her son had ALL of the T cell lineage. The balanced translocation t(1;7)(p34.1;q22) was detected in the lymphoblasts from the patient with ALL. This translocation was not seen in any other affected members of the family or in the bone marrow sample of this patient in complete remission. Taken together, t(1;7)(p34.1;q22) is thought to be one of the somatic second hits that predisposes FPD to acute leukemia with T cell phenotype.