Expansion of senescent megakaryocyte-lineage cells maintains CML cell leukemogenesis

13301甲第5255号博士（医学）金沢大学博士論文本文Full 以下に掲載：Blood Advances 4(24) pp.6175-6188 2020. American Society of Hematology. 共著者：Yamato Tanabe, Shimpei Kawamoto, Tomoiku Takaku, Soji Morishita, Atsushi Hirao, Norio Komatsu, Eiji Hara, Naofumi Mukaida, Tomohisa Bab

Chemokines as a conductor of bone marrow microenvironment in chronic myeloid leukemia

金沢大学がん進展制御研究所All blood lineage cells are generated from hematopoietic stem cells (HSCs), which reside in bone marrow after birth. HSCs self-renew, proliferate, and differentiate into mature progeny under the control of local microenvironments including hematopoietic niche, which can deliver regulatory signals in the form of bound or secreted molecules and from physical cues such as oxygen tension and shear stress. Among these mediators, accumulating evidence indicates the potential involvement of several chemokines, particularly CXCL12, in the interaction between HSCs and bone marrow microenvironments. Fusion between breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog (ABL)-1 gene gives rise to BCR-ABL protein with a constitutive tyrosine kinase activity and transforms HSCs and/or hematopoietic progenitor cells (HPCs) into disease-propagating leukemia stem cells (LSCs) in chronic myeloid leukemia (CML). LSCs can self-renew, proliferate, and differentiate under the influence of the signals delivered by bone marrow microenvironments including niche, as HSCs can. Thus, the interaction with bone marrow microenvironments is indispensable for the initiation, maintenance, and progression of CML. Moreover, the crosstalk between LSCs and bone marrow microenvironments can contribute to some instances of therapeutic resistance. Furthermore, evidence is accumulating to indicate the important roles of bone marrow microenvironment-derived chemokines. Hence, we will herein discuss the roles of chemokines in CML with a focus on bone marrow microenvironments. © 2017 by the authors. Licensee MDPI, Basel, Switzerland

Gemcitabine-induced CXCL8 expression counteracts its actions by inducing tumor neovascularization

[email protected] with pancreatic ductal adenocarcinoma (PDAC) are frequently complicated with metastatic disease or locally advanced tumors, and consequently need chemotherapy. Gemcitabine is commonly used for PDAC treatment, but with limited efficacy. The capacity of gemcitabine to generate reactive oxygen species (ROS) in human pancreatic cancer cells, prompted us to examine its effects on the expression of pro-inflammatory cytokines and chemokines. We observed that gemcitabine enhanced selectively the expression of CXCL8 in human pancreatic cancer cells through ROS generation and NF-κB activation. In vitro blocking of CXCL8 failed to modulate gemcitabine-mediated inhibition of cell proliferation in human pancreatic cancer cells. Gemcitabine also enhanced CXCL8 expression in pancreatic cancer cells in xenografted tumor tissues. Moreover, anti-CXCL8 antibody treatment in vivo attenuated tumor formation as well as intra-tumoral vascularity in nude mice, which were transplanted with Miapaca-2 cells and treated with gemcitabine. Thus, gemcitabine-induced CXCL8 may counteract the drug through inducing neovascularization

Observation and study of baryonic B decays: B -> D(*) p pbar, D(*) p pbar pi, and D(*) p pbar pi pi

We present a study of ten B-meson decays to a D(*), a proton-antiproton pair, and a system of up to two pions using BaBar's data set of 455x10^6 BBbar pairs. Four of the modes (B0bar -> D0 p anti-p, B0bar -> D*0 p anti-p, B0bar -> D+ p anti-p pi-, B0bar -> D*+ p anti-p pi-) are studied with improved statistics compared to previous measurements; six of the modes (B- -> D0 p anti-p pi-, B- -> D*0 p anti-p pi-, B0bar -> D0 p anti-p pi- pi+, B0bar -> D*0 p anti-p pi- pi+, B- -> D+ p anti-p pi- pi-, B- -> D*+ p anti-p pi- pi-) are first observations. The branching fractions for 3- and 5-body decays are suppressed compared to 4-body decays. Kinematic distributions for 3-body decays show non-overlapping threshold enhancements in m(p anti-p) and m(D(*)0 p) in the Dalitz plots. For 4-body decays, m(p pi-) mass projections show a narrow peak with mass and full width of (1497.4 +- 3.0 +- 0.9) MeV/c2, and (47 +- 12 +- 4) MeV/c2, respectively, where the first (second) errors are statistical (systematic). For 5-body decays, mass projections are similar to phase space expectations. All results are preliminary.Comment: 28 pages, 90 postscript figures, submitted to LP0

Chemokines as a Conductor of Bone Marrow Microenvironment in Chronic Myeloid Leukemia

All blood lineage cells are generated from hematopoietic stem cells (HSCs), which reside in bone marrow after birth. HSCs self-renew, proliferate, and differentiate into mature progeny under the control of local microenvironments including hematopoietic niche, which can deliver regulatory signals in the form of bound or secreted molecules and from physical cues such as oxygen tension and shear stress. Among these mediators, accumulating evidence indicates the potential involvement of several chemokines, particularly CXCL12, in the interaction between HSCs and bone marrow microenvironments. Fusion between breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog (ABL)-1 gene gives rise to BCR-ABL protein with a constitutive tyrosine kinase activity and transforms HSCs and/or hematopoietic progenitor cells (HPCs) into disease-propagating leukemia stem cells (LSCs) in chronic myeloid leukemia (CML). LSCs can self-renew, proliferate, and differentiate under the influence of the signals delivered by bone marrow microenvironments including niche, as HSCs can. Thus, the interaction with bone marrow microenvironments is indispensable for the initiation, maintenance, and progression of CML. Moreover, the crosstalk between LSCs and bone marrow microenvironments can contribute to some instances of therapeutic resistance. Furthermore, evidence is accumulating to indicate the important roles of bone marrow microenvironment-derived chemokines. Hence, we will herein discuss the roles of chemokines in CML with a focus on bone marrow microenvironments

Drastic enhancement of stable and fast domain wall motion in GdFe nanowires through laser-annealing treatment at wire edges

One of the key challenges in racetrack memory (RM) technology is achieving stable and high velocities for domain walls (DWs) while maintaining low power consumption. In our study, we propose a novel laser-annealing (LA) process to modify wire edges for a smoother DW movement along the nanowire. In this regard, a film stack of Pt (5 nm)/Gd26Fe74(20 nm)/SiN(10 nm) was deposited by magnetron sputtering. The DW velocity in the wire was measured by applying single voltage pulses and then observing the DW motion using a Kerr microscope. The current-induced domain walls motion measurements have shown that the LA process significantly enhances the velocity of DW motion. The LA of both edges of the nanowire results in a threefold increase in DW velocity compared to non-LA conditions. Further experiments illustrated that the DW velocity remains stable for the laser-annealed condition across a wide range of applied currents, spanning from 3 × 1011 to 7 × 1011 A/m2. Additionally, our investigation into the magnetic characteristics of laser-annealed nanowire regions exhibited a notable reduction of Hc at the laser-annealed edges. This decrease in Hc indicates greater ease in manipulating the material’s magnetization, which is essential for efficient DW motion. Furthermore, we explored the influence of LA on the Dzyaloshinskii–Moriya Interaction (DMI) field. The DMI finding underscores the strong correlation between DMI fields and DW speed. This achievement, i.e. the stability and consistency of the domain’s velocity (as the components of an RM) in a wide range of applied current, is significant progress in the field of operation and industrialization of RM

Functional Analysis of Novel Candidate Regulators of Insulin Secretion in the MIN6 Mouse Pancreatic β Cell Line

<div><p>Elucidating the regulation of glucose-stimulated insulin secretion (GSIS) in pancreatic β cells is important for understanding and treating diabetes. The pancreatic β cell line, MIN6, retains GSIS but gradually loses it in long-term culture. The MIN6 subclone, MIN6c4, exhibits well-regulated GSIS even after prolonged culture. We previously used DNA microarray analysis to compare gene expression in the parental MIN6 cells and MIN6c4 cells and identified several differentially regulated genes that may be involved in maintaining GSIS. Here we investigated the potential roles of six of these genes in GSIS: <i>Tmem59l</i> (Transmembrane protein 59 like), <i>Scgn</i> (Secretagogin), <i>Gucy2c</i> (Guanylate cyclase 2c), <i>Slc29a4</i> (Solute carrier family 29, member 4), <i>Cdhr1</i> (Cadherin-related family member 1), and <i>Celsr2</i> (Cadherin EGF LAG seven-pass G-type receptor 2). These genes were knocked down in MIN6c4 cells using lentivirus vectors expressing gene-specific short hairpin RNAs (shRNAs), and the effects of the knockdown on insulin expression and secretion were analyzed. Suppression of <i>Tmem59l</i>, <i>Scgn</i>, and <i>Gucy2c</i> expression resulted in significantly decreased glucose- and/or KCl-stimulated insulin secretion from MIN6c4 cells, while the suppression of <i>Slc29a4</i> expression resulted in increased insulin secretion. <i>Tmem59l</i> overexpression rescued the phenotype of the <i>Tmem59l</i> knockdown MIN6c4 cells, and immunostaining analysis indicated that the TMEM59L protein colocalized with insulin and GM130, a Golgi complex marker, in MIN6 cells. Collectively, our findings suggested that the proteins encoded by <i>Tmem59l</i>, <i>Scgn</i>, <i>Gucy2c</i>, and <i>Slc29a4</i> play important roles in regulating GSIS. Detailed studies of these proteins and their functions are expected to provide new insights into the molecular mechanisms involved in insulin secretion.</p></div

Expression of the selected candidate genes in MIN6 cells.

<p>Expression of the <i>Tmem59l</i> (A), <i>Scgn</i> (B), <i>Gucy2c</i> (C), <i>Slc29a4</i> (D), <i>Cdhr1</i> (E), and <i>Celsr2</i> (F) mRNAs in the Pr-LP, Pr-HP, C4-LP, and C4-HP MIN6 cells was examined by quantitative RT-PCR. <i>Rpl32</i> gene expression was used as an internal control. Values are the means ± SD (n = 3) of the gene expression levels relative to those in the Pr-LP MIN6 cells. **<i>P</i><0.005.</p