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pubmed: Blood[Jour]



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Smad1/5 is required for erythropoietin-mediated suppression of hepcidin in mice.
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Smad1/5 is required for erythropoietin-mediated suppression of hepcidin in mice.

Blood. 2017 Apr 24;:

Authors: Wang CY, Core AB, Canali S, Zumbrennen-Bullough KB, Ozer S, Umans L, Zwijsen A, Babitt JL

Abstract
Anemia suppresses liver hepcidin expression to supply adequate iron for erythropoiesis. Erythroferrone mediates hepcidin suppression by anemia, but its mechanism of action remains uncertain. The bone morphogenetic protein (BMP)-SMAD signaling pathway has a central role in hepcidin transcriptional regulation. Here, we explored the contribution of individual receptor-activated SMADs in hepcidin regulation and their involvement in erythroferrone suppression of hepcidin. In Hep3B cells, SMAD5 or SMAD1, but not SMAD8, knockdown inhibited hepcidin (HAMP) mRNA expression. Hepatocyte-specific double-knockout Smad1(fl/fl);Smad5(fl/fl);Cre+ mice exhibited ~90% transferrin saturation and massive liver iron overload, whereas Smad1(fl/fl);Smad5(fl/wt);Cre+ mice or Smad1(fl/wt);Smad5(fl/fl);Cre+ females containing one functional Smad5 or Smad1 allele had modestly increased serum and liver iron, and single-knockout Smad5(fl/fl);Cre+ or Smad1(fl/fl);Cre+ mice had minimal to no iron loading, suggesting a gene dosage effect. Hamp mRNA was reduced in all Cre+ mouse livers at 12 days and in all Cre+ primary hepatocytes. However, only double-knockout mice continued to exhibit low liver Hamp at 8 weeks and failed to induce Hamp in response to Bmp6 in primary hepatocyte cultures. Epoetin alfa (EPO) robustly induced bone marrow erythroferrone (Fam132b) mRNA in control and Smad1(fl/fl);Smad5(fl/fl);Cre+ mice, but suppressed hepcidin only in control mice. Likewise, erythroferrone failed to decrease Hamp mRNA in Smad1(fl/fl);Smad5(fl/fl);Cre+ primary hepatocytes and SMAD1/SMAD5 knockdown Hep3B cells. EPO and erythroferrone reduced liver Smad1/5 phosphorylation in parallel with Hamp mRNA in control mice and Hep3B cells. Thus, Smad1 and Smad5 have overlapping functions to govern hepcidin transcription. Moreover, erythropoietin and erythroferrone target Smad1/5 signaling and require Smad1/5 to suppress hepcidin expression.

PMID: 28438754 [PubMed - as supplied by publisher]




FLI1 level during megakaryopoiesis affects thrombopoiesis and platelet biology.
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FLI1 level during megakaryopoiesis affects thrombopoiesis and platelet biology.

Blood. 2017 Apr 21;:

Authors: Vo KK, Jarocha DJ, Lyde RB, Hayes V, Thom CS, Sullivan SK, French DL, Poncz M

Abstract
Friend Leukemia Virus Integration 1 (FLI1), a critical transcription factor (TF) during megakaryocyte differentiation, is amongst genes hemizygously deleted in Jacobsen syndrome, resulting in a macrothrombocytopenia termed Paris-Trousseau syndrome (PTSx). Recently, heterozygote human FLI1 mutations have been ascribed to cause thrombocytopenia. We studied induced-pluripotent stem cell (iPSC)-derived megakaryocytes (iMegs) to better understand these clinical disorders, beginning with iPSCs generated from a PTSx patient and iPSCs from a control line with a targeted heterozygous FLI1 knockout (FLI1(+/-)). PTSx and FLI1(+/-) iMegs replicate many of the described megakaryocyte/platelet features including a decrease in iMeg yield and fewer platelets released per iMeg. Platelets released in vivo from infusion of these iMegs had poor half-lives and functionality. We noted that the closely-linked ETS Proto-Oncogene 1 (ETS1) is over-expressed in these FLI1-deficient iMegs, suggesting that FLI1 negatively regulates ETS1 in megakaryopoiesis. Finally, we examined whether FLI1 overexpression would affect megakaryopoiesis and thrombopoiesis. We found increased yield of non-injured, in vitro iMeg yield and increased in vivo yield, half-life and functionality of released platelets. These studies confirm FLI1 heterozygosity results in pleiotropic defects similar to those noted with other critical megakaryocyte-specific TFs; however, unlike those TFs, FLI1 overexpression improved yield and functionality.

PMID: 28432223 [PubMed - as supplied by publisher]




Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma.
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Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma.

Blood. 2017 Apr 21;:

Authors: Rasche L, Angtuaco E, McDonald JE, Buros A, Stein C, Pawlyn C, Thanendrarajan S, Schinke C, Samant R, Yaccoby S, Walker B, Epstein J, Zangari M, van Rhee F, Meissner T, Goldschmidt H, Hemminki K, Houlston R, Barlogie B, Davies FE, Morgan GJ, Weinhold N

Abstract
18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) and diffusion weighted magnetic resonance imaging with background signal suppression (DWIBS) are two powerful functional imaging modalities in the evaluation of the malignant plasma cell (PC) disease multiple myeloma (MM). Preliminary observations have suggested that MM patients with extensive disease according to DWIBS may be reported as being disease-free on FDG-PET ("PET-false-negative"). The aim of this study was to describe the proportion of PET-false-negativity in a representative set of 227 newly diagnosed MM patients with simultaneous assessment of FDG-PET and DWIBS, and to identify tumor-intrinsic features associated with this pattern. We found the incidence of PET-false-negativity to be 11%. Neither tumor-load associated parameters, such as the degree of bone marrow PC infiltration, nor the PC proliferation rate were associated with this subset. However, the gene coding for Hexokinase-2, which catalyzes the first step of glycolysis, was significantly lower expressed in PET false-negative cases (5.3-fold change, P<0.001) which provides a mechanistic explanation for this feature. In conclusion, we demonstrate a relevant number of patients with FDG-PET false-negative MM and a strong association between Hexokinase-2 expression and this negativity; a finding which may also be relevant for clinical imaging of other hematological cancers.

PMID: 28432222 [PubMed - as supplied by publisher]




Biological considerations of plasma-derived and recombinant factor VIII immunogenicity.
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Biological considerations of plasma-derived and recombinant factor VIII immunogenicity.

Blood. 2017 Apr 21;:

Authors: Lai J, Hough C, Tarrant J, Lillicrap D

Abstract
In hemophilia A, the most severe complication of factor VIII (FVIII) replacement therapy involves the formation of FVIII neutralizing antibodies, also known as inhibitors, in 25-30% of patients. This adverse event is associated with a significant increase in morbidity and economic burden, thus highlighting the need to identify methods to limit FVIII immunogenicity. Inhibitor development is regulated by a complex balance of genetic factors, such as FVIII genotype, and environmental variables, such as coexistent inflammation. One of the hypothesized risk factors of inhibitor development is the source of the FVIII concentrate, either from recombinant or plasma-derived sources. Differential immunogenicity of these concentrates has been documented in several recent epidemiological studies, generating significant debate within the hemophilia treatment community. To date, these discussions have been unable to reach a consensus as to how these outcomes might be integrated into enhancing clinical care. Moreover, the biological mechanistic explanations for the observed differences are poorly understood. In this Perspective, we complement the existing epidemiological investigations with an overview of the range of possible biochemical and immunological mechanisms that may contribute to the different immune outcomes observed with plasma-derived and recombinant FVIII products.

PMID: 28432221 [PubMed - as supplied by publisher]




miR-155 promotes FLT3-ITD-induced myeloproliferative disease through inhibition of the interferon response.
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miR-155 promotes FLT3-ITD-induced myeloproliferative disease through inhibition of the interferon response.

Blood. 2017 Apr 21;:

Authors: Wallace JA, Kagele DA, Eiring AM, Kim CN, Hu R, Runtsch MC, Alexander M, Huffaker TB, Lee SH, Patel AB, Mosbruger TL, Voth W, Rao DS, Miles RR, Round JL, Deininger MW, O'Connell RM

Abstract
FLT3-ITD(+) AML accounts for approximately 25% of all AML cases, and is a subtype that carries a poor prognosis. miR-155 is specifically overexpressed in FLT3-ITD(+) AML compared to FLT3-WT AML, and is critical for the growth of FLT3-ITD(+) AML cells in vitro. However, miR-155's role in regulating FLT3-ITD-mediated disease in vivo remains unclear. In this study, we utilized a genetic mouse model to determine whether miR-155 influences the development of FLT3-ITD-induced myeloproliferative disease. Results indicate that miR-155 promotes FLT3-ITD-induced myeloid expansion in the bone marrow, spleen, and peripheral blood. Mechanistically, miR-155 increases proliferation of the hematopoietic stem and progenitor cell compartments by reducing the growth-inhibitory effects of the interferon response, and this involves targeting of Cebpb. Consistent with our observations in mice, primary FLT3-ITD(+) AML clinical samples have significantly higher miR-155 levels and a lower interferon response compared to FLT3-WT AML samples. Further, inhibition of miR-155 in FLT3-ITD(+) AML cell lines using CRISPR/Cas9, or primary FLT3-ITD(+) AML samples using LNA antisense inhibitors, results in an elevated interferon response and reduces colony formation. Altogether, our data reveal that miR-155 collaborates with FLT3-ITD to promote myeloid cell expansion in vivo, and that this involves a multi-target mechanism that includes repression of interferon signaling.

PMID: 28432220 [PubMed - as supplied by publisher]