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pubmed: Blood[Jour]



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TGF-β-induced intracellular PAI-1 is responsible for retaining hematopoietic stem cells in the niche.
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TGF-β-induced intracellular PAI-1 is responsible for retaining hematopoietic stem cells in the niche.

Blood. 2017 Aug 18;:

Authors: Yahata T, Ibrahim AA, Muguruma Y, Eren M, Shaffer AM, Watanabe N, Kaneko S, Nakabayashi T, Dan T, Hirayama N, Vaughan DE, Miyata T, Ando K

Abstract
Hematopoietic stem and progenitor cells (HSPCs) reside in the supportive stromal niche in bone marrow (BM); when needed, however, they are rapidly mobilized into the circulation, suggesting that HSPCs are intrinsically highly motile but are usually stayed in the niche. We questioned what determines the motility of HSPCs. Here we show that transforming growth factor (TGF)-β-induced intracellular plasminogen activator inhibitor (PAI)-1 activation is responsible for keeping HSPCs in the BM niche. We found that the expression of PAI-1, a downstream target of TGF-β-signaling, was selectively augmented in niche-residing HSPCs. Functional inhibition of the TGF-β-PAI-1 signal increased MT1-MMP-dependent cellular motility, causing a detachment of HSPCs from the TGF-β-expressing niche cells, such as megakaryocytes. Furthermore, consistently high motility in PAI-1-deficient HSPCs was demonstrated by both a trans-well migration assay and reciprocal transplantation experiments, indicating that intracellular, not extracellular, PAI-1 suppresses the motility of HSPCs, thereby causing them to stay in the niche. Mechanistically, intracellular PAI-1 inhibited the proteolytic activity of proprotein convertase Furin, diminishing MT1-MMP activity. This reduced expression of MT1-MMP in turn affected the expression levels of several adhesion/de-adhesion molecules for determination of HSPC localization, such as CD44, VLA-4, and CXCR4, which then promoted the retention of HSPCs in the niche. Our findings open up a new field for the study of intracellular proteolysis as a regulatory mechanism of stem cell fate, which has the potential to improve clinical HSPC mobilization and transplantation protocols.

PMID: 28821477 [PubMed - as supplied by publisher]




TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy.
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TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy.

Blood. 2017 Aug 17;:

Authors: Eskelund CW, Dahl C, Hansen JW, Westman M, Kolstad A, Pedersen LB, Montano-Almendras CP, Husby S, Freiburghaus C, Ek S, Pedersen A, Niemann C, Räty R, Brown P, Geisler CH, Andersen MK, Guldberg P, Jerkeman M, Grønbæk K

Abstract
Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable and we are still unable to identify patients who will not benefit from the current standard-of-care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger MCL patients from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53 (11%) and NOTCH1 (4%), and deletions of TP53 (16%) and CDKN2A (20%) were significantly associated with inferior outcomes (together with MIPI, MIPI-c, Blastoid morphology and Ki67>30%); however, in multivariate analyses only TP53 mutations (HR=6.2, p<0.0001) retained prognostic impact for overall survival (OS), while TP53 mutations (HR=6.9, p<0.0001) and MIPI-c high-risk (HR=2.6, p=0.003) had independent prognostic impact on time to relapse. TP53-mutated cases had a dismal outcome with a median OS of 1.8 years and 50% relapsed at 1.0 years (compared to not reached (NR) and 12.7 years, respectively, for TP53-unmutated cases, p<0.0001). TP53 mutations were significantly associated with Ki67>30%, blastoid morphology, MIPI high-risk and inferior responses to both induction- and high-dose chemotherapy. In conclusion, we show that TP53 mutations identify a phenotypically distinct and highly aggressive form of MCL with poor or no response to regimens including cytarabine, rituximab and autologous stem-cell transplant (ASCT). We suggest that MCL patients should be stratified according to TP53 status, and that patients with TP53 mutations should be considered for experimental frontline trials exploring novel agents.

PMID: 28819011 [PubMed - as supplied by publisher]




SF3B1 mutation arises at the multipotent HSC level.
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SF3B1 mutation arises at the multipotent HSC level.

Blood. 2017 Aug 17;130(7):955

Authors:

PMID: 28818982 [PubMed - in process]




Putti MC, Pizzi M, Bertozzi I, et al. Bone marrow histology for the diagnosis of essential thrombocythemia in children: a multicenter Italian study. Blood. 2017;129(22):3040-3042.
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Putti MC, Pizzi M, Bertozzi I, et al. Bone marrow histology for the diagnosis of essential thrombocythemia in children: a multicenter Italian study. Blood. 2017;129(22):3040-3042.

Blood. 2017 Aug 17;130(7):954

Authors:

PMID: 28818981 [PubMed - in process]




Relapse of an acute leukemia of mixed lineage as an isolated orbital mass.
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Relapse of an acute leukemia of mixed lineage as an isolated orbital mass.

Blood. 2017 Aug 17;130(7):953

Authors: Zhou XY, Behdad A

PMID: 28818980 [PubMed - in process]




Incidental brown adipose tissue in bone marrow biopsy.
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Incidental brown adipose tissue in bone marrow biopsy.

Blood. 2017 Aug 17;130(7):952

Authors: Chapman J, Vega F

PMID: 28818979 [PubMed - in process]




Innately interesting interactions.
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Innately interesting interactions.

Blood. 2017 Aug 17;130(7):844-845

Authors: Komanduri KV

PMID: 28818978 [PubMed - in process]




Accept the complement (blockade).
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Accept the complement (blockade).

Blood. 2017 Aug 17;130(7):842-843

Authors: Davies SM

PMID: 28818977 [PubMed - in process]




Splicing together the origins of MDS-RS.
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Splicing together the origins of MDS-RS.

Blood. 2017 Aug 17;130(7):841-842

Authors: Meyer SE

PMID: 28818976 [PubMed - in process]




Inherited thrombocytopenia and Occam's razor.
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Inherited thrombocytopenia and Occam's razor.

Blood. 2017 Aug 17;130(7):839-840

Authors: Lipton JM

PMID: 28818975 [PubMed - in process]




The Role of Anthracycline and Comprehensive Geriatric Assessment for Elderly Patients with Diffuse Large B-cell Lymphoma.
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The Role of Anthracycline and Comprehensive Geriatric Assessment for Elderly Patients with Diffuse Large B-cell Lymphoma.

Blood. 2017 Aug 16;:

Authors: Lin RJ, Behera M, Diefenbach CS, Flowers CR

PMID: 28814386 [PubMed - as supplied by publisher]