[Acute promyelocytic leukemia recurrence diagnosed due to granulocytic sarcoma of the external auditory canal].

A 47-year-old man was diagnosed with acute promyelocytic leukemia (APL) accompanied by pancytopenia and left forearm swelling. Complete remission was achieved with remission induction therapy using all-trans retinoic acid (ATRA), and consolidation therapy was completed. Three months after the treatment, left ear closure was observed, and a mass lesion was found in the left external auditory canal. An initial tumor biopsy only revealed inflammatory cell infiltration. Moreover, the tumor's rebiopsy performed 3 months later revealed MPO-positive and CD68-positive granulocyte infiltration. Furthermore, the rebiopsy revealed 4.9×105 copies/µgRNA of PML/RARα, the patient was diagnosed with locally recurrent APL. A bone marrow examination 2 weeks later confirmed an increase in myeloblasts and promyelocytes for the first time since the confirmation of remission. Therefore, it was diagnosed as bone marrow recurrence. Reinduction therapy using ATRA and arsenic trioxide again led to complete remission, after which autologous peripheral blood stem cell transplantation was performed. Currently, complete remission is being maintained. In this case, the recurrence of the external auditory canal lesion preceded the bone marrow recurrence. Therefore, it is important to note the nonspecific leukemia recurrence patterns of the external auditory canal.

Pre-Transplantation Blockade of TNF-α-Mediated Oxygen Species Accumulation Protects Hematopoietic Stem Cells.

Hematopoietic stem cell (HSC) transplantation (HSCT) for malignancy requires toxic pre-conditioning to maximize anti-tumor effects and donor-HSC engraftment. While this induces bone marrow (BM)-localized inflammation, how this BM environmental change affects transplanted HSCs in vivo remains largely unknown. We here report that, depending on interval between irradiation and HSCT, residence within lethally irradiated recipient BM compromises donor-HSC reconstitution ability. Both in vivo and in vitro we demonstrate that, among inflammatory cytokines, TNF-α plays a role in HSC damage: TNF-α stimulation leads to accumulation of reactive oxygen species (ROS) in highly purified hematopoietic stem/progenitor cells (HSCs/HSPCs). Transplantation of flow-cytometry-sorted murine HSCs reveals damaging effects of accumulated ROS on HSCs. Short-term incubation either with an specific inhibitor of tumor necrosis factor receptor 1 signaling or an antioxidant N-acetyl-L-cysteine (NAC) prevents TNF-α-mediated ROS accumulation in HSCs. Importantly, pre-transplantation exposure to NAC successfully demonstrats protective effects in inflammatory BM on graft-HSCs, exhibiting better reconstitution capability than that of nonprotected control grafts. We thus suggest that in vivo protection of graft-HSCs from BM inflammation is a feasible and attractive approach, which may lead to improved hematopoietic reconstitution kinetics in transplantation with myeloablative conditioning that inevitably causes inflammation in recipient BM. Stem Cells 2017;35:989-1002.

Stage-specific roles for CXCR4 signaling in murine hematopoietic stem/progenitor cells in the process of bone marrow repopulation.

Hematopoietic cell transplantation has proven beneficial for various intractable diseases, but it remains unclear how hematopoietic stem/progenitor cells (HSPCs) home to the bone marrow (BM) microenvironment, initiate hematopoietic reconstitution, and maintain life-long hematopoiesis. The use of newly elucidated molecular determinants for overall HSPC engraftment should benefit patients. Here, we report that modification of C-X-C chemokine receptor type 4 (Cxcr4) signaling in murine HSPCs does not significantly affect initial homing/lodging events, but leads to alteration in subsequent BM repopulation kinetics, with observations confirmed by both gain- and loss-of-function approaches. By using C-terminal truncated Cxcr4 as a gain-of-function effector, we demonstrated that signal augmentation likely led to favorable in vivo repopulation of primitive cell populations in BM. These improved features were correlated with enhanced seeding efficiencies in stromal cell cocultures and altered ligand-mediated phosphorylation kinetics of extracellular signal-regulated kinases observed in Cxcr4 signal-augmented HSPCs in vitro. Unexpectedly, however, sustained signal enhancement even with wild-type Cxcr4 overexpression resulted in impaired peripheral blood (PB) reconstitution, most likely by preventing release of donor hematopoietic cells from the marrow environment. We thus conclude that timely regulation of Cxcr4/CXCR4 signaling is key in providing donor HSPCs with enhanced repopulation potential following transplantation, whilst preserving the ability to release HSPC progeny into PB for improved transplantation outcomes.

Digital gene atlas of neonate common marmoset brain.

Interest in the common marmoset (Callithrix jacchus) as a primate model animal has grown recently, in part due to the successful demonstration of transgenic marmosets. However, there is some debate as to the suitability of marmosets, compared to more widely used animal models, such as the macaque monkey and mouse. Especially, the usage of marmoset for animal models of human cognition and mental disorders, is still yet to be fully explored. To examine the prospects of the marmoset model for neuroscience research, the Marmoset Gene Atlas (https://gene-atlas.bminds.brain.riken.jp/) provides a whole brain gene expression atlas in the common marmoset. We employ in situ hybridization (ISH) to systematically analyze gene expression in neonate marmoset brains, which allows us to compare expression with other model animals such as mouse. We anticipate that these data will provide sufficient information to develop tools that enable us to reveal marmoset brain structure, function, cellular and molecular organization for primate brain research.

Successful treatment of a patient with POEMS syndrome by tandem high-dose chemotherapy with autologous CD34+ purged stem cell rescue.

A 36-year-old man was admitted because of numbness and muscle weakness in the lower extremities. He had gait disturbance, malaise, and body weight loss. Based on the existence of monoclonal gammopathy, the proliferation of abnormal plasma cells in the bone marrow, the presence of sclerotic bone lesion, polycythemia, mild splenomegaly, and an elevated level of serum vascular endothelial growth factor (VEGF) (14,900 pg/mL; normal, 62-707), he was diagnosed as having peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. Following 2 courses of conventional chemotherapy with doxorubicin and dexamethasone, peripheral blood stem cells were mobilized by high-dose etoposide (500 mg/m(2) x 3 days) and granulocyte colony-stimulating factor. After purging by CD34+ selection using the CliniMACS device, the selected cells (12.4 x 10(6)/kg) were cryopreserved. He was then treated with tandem high-dose chemotherapy (HDC) (melphalan 100 mg/m(2) x 2 days) with autologous stem cell rescue. After the first course of HDC, the serum level of VEGF normalized and the minimal residual disease in the bone marrow was reduced below the detection limit of CDR3 analysis by polymerase chain reaction. The patient has been in remission for more than 20 months. He has gradually recovered from the neurological symptoms and now has no impairments of daily living. Our experience suggests that autologous purged stem cell transplantation should be considered as the treatment of choice for POEMS syndrome.

Functional characterization of hematopoietic stem cells in the spleen.

OBJECTIVE: Hematopoietic stem cells (HSCs) reside in both bone marrow (BM) and spleen in adult mice. However, whether BM and spleen HSCs are functionally similar is not known. Spleen HSCs were compared with BM HSCs by various assays. MATERIALS AND METHODS: Whole BM and spleen cells were quantitatively analyzed by competitive repopulation. Single-cell transplantation was performed with HSCs purified from BM and spleen. A parabiosis model was used to distinguish organ-specific HSCs from circulating HSCs. The cell cycle was analyzed with pyronin Y staining and bromodeoxyuridine uptake. RESULTS: Repopulating and self-renewal potentials were similar on a clonal basis between BM and spleen HSCs, whereas the HSC frequency in the spleen was significantly lower than that in the BM. Analysis of parabiotic mice suggested that most HSCs are long-term residents in each organ. Cell-cycle analysis revealed that spleen HSCs cycle twice as frequently as do BM HSCs, suggesting that G(0) phase length is longer in BM HSCs than in spleen HSCs. The cycling difference between BM and spleen HSCs was also observed in mice that had been reconstituted with BM or spleen cells, suggesting that HSC quiescence is regulated in an organ-specific manner. CONCLUSIONS: Spleen HSCs and BM HSCs are functionally similar, but their cycling behaviors differ.