The Mst1 and 2 cytosolic serine/threonine protein kinases are the mammalian orthologs of the Drosophila Hippo protein. Mst1 has been shown previously to participate in T-cell and B-cell trafficking and the migration of lymphocytes into secondary lymphoid organs in a cell-intrinsic manner. We show here that the absence of Mst1 alone only modestly impacts B cell homing to lymph nodes. The absence of both Mst1 and 2 in hematopoietic cells results in relatively normal B cell development in the bone marrow and does not impact migration of immature B cells to the spleen. However follicular B cells lacking both Mst1 and Mst2 mature in the splenic white pulp but are unable to recirculate to lymph nodes or to the bone marrow. These cells also cannot traffic to the splenic red pulp. The inability of late transitional and follicular B cells lacking Mst 1 and 2 to migrate to the red pulp explains their failure to differentiate into marginal zone B cell precursors and marginal zone B cells. Mst1 and Mst2 are therefore required for follicular B cells to acquire the ability to recirculate and also to migrate to the splenic red pulp in order to generate marginal zone B cells. In addition B-1 a B cell development is defective in the absence of Mst1.
Purpose of review Gfi-1, originally identified as a transcriptional repressor in lymphoid cells, is now recognized to have essential, independent functions in neutrophil maturation and hematopoietic stem cell biology. Here we review recent studies pertaining to Gfi-1 and its cell context specific functions in hematopoietic development. Recent findings Progress in mapping the precise timing of requirements for myeloid transcription factors during hematopoietic development reveals a more refined picture of their sequence of action. We contrast Gfi-1's role in neutrophil development with PU.1, C/EBPα, and C/EBPε. Gfi-1 has been found to be a major regulator of adult hematopoietic stem cells. It is required for restricting the proliferation of hematopoietic stem cells and maintaining their functional integrity. We discuss its role and compare its function with that of other regulators recently implicated in the biology of hematopoietic stem cells. Summary Considerable progress has been made in understanding Gfi-1's context-sensitive roles at defined stages of hematopoietic differentiation.
We sought to assess the safety of adding ixazomib, an oral proteasome inhibitor, to a multi-agent treatment regimen for older adults with acute lymphoblastic leukemia (ALL). Patients 51 to 75 years of age with newly diagnosed ALL were screened. Induction consisted of prednisone (P), vincristine (V), and doxorubicin (D). For BCR-ABL1+ patients, dasatinib was added. On Days 1, 8, 15 of induction, ixazomib was given orally. After induction patients received 1 cycle of consolidation in which ixazomib was given on Days 1, 8, 15. After consolidation, patients in remission (CR) were offered stem cell transplantation. Among the 19 patients treated, 15 (79%) [90% CI, 58–92%] achieved CR or CRi. At 2 years, the overall survival was 47% [95%CI, 29–72%]. In this study the dose of 2.3 mg of ixazomib in combination was the MTD for older patients with ALL and is the recommended dose for future phase 2 studies.
Abstract The molecular events during the anti‐tumor response induced by interleukin (IL)‐4 were investigated by quantitative polymerase chain reaction. The growth of Chinese hamster ovary cells transfected to produce IL‐4 (CHO.T1) was strongly suppressed when cells were injected intraperitoneally into nude mice and this suppression was accompanied by the rapid accumulation of activated macro‐phages. Peritoneal cells from such mice were analyzed for mRNA induced by IL‐4. Correlating with a high local IL‐4 concentration, several transcripts were found to be up‐regulated during the early phase of the anti‐tumor response [IL‐4 receptor, IL‐5, tumor necrosis factor (TNF) and interferon (IFN)‐γ]. The functional relevance of the elevated mRNA levels was analyzed by injection of CHO.T1 cells together with anti‐cytokine monoclonal antibodies (mAb). In contrast to anti‐IL‐5 and anti‐TNF mAb, an anti‐IFN‐γ mAb interfered with the anti‐tumor response demonstrating the involvement of IFN‐γ during the IL‐4‐induced tumor suppression. Tumor growth in anti‐IFN‐γ mAb‐treated animals was significantly delayed in comparison to anti‐IL‐4 mAb‐treated mice, suggesting that IFN‐γ‐independent effector cells may also be involved.
Abstract In order to analyze the effect of a high local concentration of macrophage colony‐stimulating factor (M‐CSF; CSF‐1) on tumor growth, the plasmacytoma cell line J558L was transfected with the human M‐CSF gene and injected into syngeneic BALB/c mice. In contrast to the parental tumors, M‐CSF transfectants were heavily infiltrated by macrophages as evidenced by immunohistochemistry with antibodies to Mac‐1 and Mac‐3 and by isolation of the macrophages from the tumor. Nevertheless, tumor growth was only slightly affected by M‐CSF and M‐CSF‐producing cells grew as tumor in all cases. The growth retardation of M‐CSF‐producing cells varied depending on the experiment and seemed to be due to an indirect effect because the growth rate of the cells in vitro had not changed upon gene transfer. Attempts to activate the tumor‐infiltrating macrophages for tumor suppression by systemic application of interferon‐γ and/or lipopolysaccharide were not successful. Altogether, our results suggest that M‐CSF is a potent chemoattractant for macrophages in vivo but alone is not sufficient to activate these macrophages for tumoricidal activity.
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