A Transmission-Line-Based Cochlear Standing Wave Model To Elucidate Mechanism of Human Auditory System.

How do people hear sounds? As a counterpart of Prof. G. V. Békésy's traveling wave theory, we have proposed resonance theory of outer hair cells and cochlear standing wave theory, respectively. Based on these proposals, this paper develops a transmission-line-based cochlear standing wave model. Since the macroscopic cochlear model is designed as it looks like, various auditory physiology can be explained. Transient analyses with pure-tone excitation and Gaussian pulse excitation are carried out, and Prof. D. Kemp's otoacoustic emission (OAE) is demonstrated successfully.Clinical relevance-Our new model has a great potential to explain auditory physiology including structural inner disorders, hearing loss, and even tinnitus.

Usefulness of Silent MR Angiography for Intracranial Aneurysms Treated with a Flow-Diverter Device.

BACKGROUND AND PURPOSE: The flow-diverter device has been established as a treatment procedure for large unruptured intracranial aneurysms. The purpose of this study was to compare the usefulness of Silent MR angiography and time-of-flight MRA to assess the parent artery and the embolization state of the aneurysm after a flow-diverter placement. MATERIALS AND METHODS: Seventy-eight large, unruptured internal carotid aneurysms in 78 patients were the subjects of this study. After 6 months of treatment, they underwent follow-up digital subtraction angiography, Silent MRA, and TOF-MRA, performed simultaneously. All images were independently reviewed by 2 neurosurgeons and 1 radiologist and rated on a 4-point scale from 1 (not visible) to 4 (excellent) to evaluate the parent artery. The aneurysmal embolization status was assessed with 2 ratings: complete or incomplete occlusion. RESULTS: The mean scores of Silent MRA and TOF-MRA regarding the parent artery were 3.18 ± 0.72 and 2.31 ± 0.86, respectively, showing a significantly better score with Silent MRA (P < .01). In the assessment of the embolization of aneurysms on Silent MRA and TOF-MRA compared with DSA, the percentages of agreement were 91.0% and 80.8%, respectively. CONCLUSIONS: Silent MRA is superior for visualizing blood flow images inside flow-diverter devices compared with TOF-MRA. Furthermore, Silent MRA enables the assessment of aneurysmal embolization status. Silent MRA is useful for assessing the status of large and giant unruptured internal carotid aneurysms after flow-diverter placement.

Arrhythmogenic response to isoproterenol testing vs. exercise testing in arrhythmogenic right ventricular cardiomyopathy patients.

Aims: To compare the arrhythmic response to isoproterenol and exercise testing in newly diagnosed arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. Methods and results: We studied isoproterenol [continuous infusion (45 µg/min) for 3 min] and exercise testing (workload increased by 30 W every 3 min) performed in consecutive newly diagnosed ARVC patients. Both tests were evaluated with regard to the incidence of (i) polymorphic premature ventricular contractions (PVCs) and couplet(s) or (ii) sustained or non-sustained ventricular tachycardia (VT) with left bundle branch block [excluding right ventricular outflow tract VT]; and compared to a control group referred for the evaluation of PVCs without structural heart disease. Thirty-seven ARVC patients (63.5% male, age 38 ± 16 years) were included. The maximal sinus rhythm heart rate achieved during isoproterenol testing was significantly lower compared to exercise testing (149 ± 17 bpm vs. 166 ± 19 bpm, P < 0.0001). However, the incidence of polymorphic ventricular arrhythmias was much higher during isoproterenol testing compared to exercise testing [33/37 (89.2%) vs. 16/37 (43.2%), P < 0.0001]. Interestingly, isoproterenol testing was arrhythmogenic in all 15 patients in whom baseline PVCs were reduced or suppressed during exercise testing. During both isoproterenol and exercise testing, control group presented a low incidence of ventricular arrhythmias compared to ARVC patients (8.1% vs. 89.2%, P < 0.0001 and 2.7% vs. 43.2%, P < 0.0001, respectively). Conclusions: The incidence of polymorphic ventricular arrhythmias is significantly higher during isoproterenol compared to exercise testing in newly diagnosed ARVC patients, suggesting its potential utility for the diagnosis.

The impact of external fixation on mortality in patients with an unstable pelvic ring fracture: a propensity-matched cohort study.

AIM: There is not adequate evidence to establish whether external fixation (EF) of pelvic fractures leads to a reduced mortality. We used the Japan Trauma Data Bank database to identify isolated unstable pelvic ring fractures to exclude the possibility of blood loss from other injuries, and analyzed the effectiveness of EF on mortality in this group of patients. PATIENTS AND METHODS: This was a registry-based comparison of 1163 patients who had been treated for an isolated unstable pelvic ring fracture with (386 patients) or without (777 patients) EF. An isolated pelvic ring fracture was defined by an Abbreviated Injury Score (AIS) for other injuries of < 3. An unstable pelvic ring fracture was defined as having an AIS ≥ 4. The primary outcome of this study was mortality. A subgroup analysis was carried out for patients who required blood transfusion within 24 hours of arrival in the Emergency Department and those who had massive blood loss (AIS code: 852610.5). Propensity-score matching was used to identify a cohort like the EF and non-EF groups. RESULTS: With the use of propensity-score matching using the completed data, 346 patients were matched. When the propensity-score matching was adjusted, EF was associated with a significantly lower risk of death (p = 0.047). In the subgroup analysis of patients who needed blood transfusion within 24 hours and those who had massive blood loss, EF was associated with a significantly lower risk of death in patients who needed blood transfusion within 24 hours (p = 0.014) and in those with massive blood loss (p = 0.016). CONCLUSION: The use of EF to treat unstable pelvic ring fractures was associated with a significantly lower risk of death, especially in patients with severe fractures. Cite this article: Bone Joint J 2018;100-B:233-41.

High expression of ABCG2 induced by EZH2 disruption has pivotal roles in MDS pathogenesis.

Both proto-oncogenic and tumor-suppressive functions have been reported for enhancer of zeste homolog 2 (EZH2). To investigate the effects of its inactivation, a mutant EZH2 lacking its catalytic domain was prepared (EZH2-dSET). In a mouse bone marrow transplant model, EZH2-dSET expression in bone marrow cells induced a myelodysplastic syndrome (MDS)-like disease in transplanted mice. Analysis of these mice identified Abcg2 as a direct target of EZH2. Intriguingly, Abcg2 expression alone induced the same disease in the transplanted mice, where stemness genes were enriched. Interestingly, ABCG2 expression is specifically high in MDS patients. The present results indicate that ABCG2 de-repression induced by EZH2 mutations have crucial roles in MDS pathogenesis.

Incidence of elevated procalcitonin and presepsin levels after severe trauma: a pilot cohort study.

Procalcitonin (PCT) and presepsin (PSEP) are useful biomarkers for diagnosing sepsis; however, elevated PCT and PSEP levels may be observed in conditions other than sepsis. We hypothesised that PCT and PSEP levels could increase after severe traumatic injuries. Trauma patients with an Injury Severity Score of ≥16 from October 2013 to September 2015 were enrolled in our study. We examined PCT and PSEP levels and their positive rates on days 0 and 1. PCT and PSEP levels on days 0 and 1 were compared. Risk factors for increasing sepsis biomarker levels were identified by multivariate logistic regression analyses. In this study, 75 patients were included. PCT levels on days 0 and 1 were 0.1±0.4 and 1.8±6.3 ng/ml, respectively (P=0.02). PSEP levels on days 0 and 1 were 221±261 and 222±207 pg/ml, respectively (P=0.98). As per multivariate logistic regression analyses, packed red blood cell (PRBC) transfusion was the only independent risk factor for higher PCT levels on day 1 (P=0.04). Using PCT to diagnose sepsis in trauma patients on day 1 requires caution. PRBC transfusion was found to be a risk factor for increasing PCT levels. On the other hand, PSEP levels were not affected by trauma during the early phases.

Protease-activated receptor-1 inhibits proliferation but enhances leukemia stem cell activity in acute myeloid leukemia.

Eradication of leukemia stem cells (LSCs) is the ultimate goal of treating acute myeloid leukemia (AML). We recently showed that the combined loss of Runx1/Cbfb inhibited the development of MLL-AF9-induced AML. However, c-Kit+/Gr-1- cells remained viable in Runx1/Cbfb-deleted cells, indicating that suppressing RUNX activity may not eradicate the most immature LSCs. In this study, we found upregulation of several hemostasis-related genes, including the thrombin-activatable receptor PAR-1 (protease-activated receptor-1), in Runx1/Cbfb-deleted MLL-AF9 cells. Similar to the effect of Runx1/Cbfb deletion, PAR-1 overexpression induced CDKN1A/p21 expression and attenuated proliferation in MLL-AF9 cells. To our surprise, PAR-1 deficiency also prevented leukemia development induced by a small number of MLL-AF9 leukemia stem cells (LSCs) in vivo. PAR-1 deficiency also reduced leukemogenicity of AML1-ETO-induced leukemia. Re-expression of PAR-1 in PAR-1-deficient cells combined with a limiting-dilution transplantation assay demonstrated the cell-dose-dependent role of PAR-1 in MLL-AF9 leukemia: PAR-1 inhibited rapid leukemic proliferation when there were a large number of LSCs, while a small number of LSCs required PAR-1 for their efficient growth. Mechanistically, PAR-1 increased the adherence properties of MLL-AF9 cells and promoted their engraftment to bone marrow. Taken together, these data revealed a multifaceted role for PAR-1 in leukemogenesis, and highlight this receptor as a potential target to eradicate primitive LSCs in AML.

Expressions of isopeptide bonds and corneodesmosin in middle ear cholesteatoma.

OBJECTIVE: Isopeptide bonds form cross-links between constituent proteins in the horny layer of the epidermis. Corneodesmosin (CDSN) is a major component of corneodesmosomes, which bind corneocytes together. Both play important roles in maintaining epidermal barrier functions. In the present study, we investigated the expressions of isopeptide bonds, CDSN, and related enzymes in middle ear cholesteatoma in comparison with the skin. DESIGN: Prospective case series of patients with middle ear cholesteatoma. SETTING: Tertiary medical institute. PARTICIPANTS: Cholesteatoma and normal postauricular skin were collected from patients with acquired middle ear cholesteatoma during tympanomastoidectomy. MAIN OUTCOME MEASURES: Expression of e-(g-glutamyl)lysine isopeptide bonds was examined by immunohistochemistry; Expressions of transglutaminase (TGase)1, TGase2, TGase3, and TGase5 by immunohistochemistry and quantitative RT-PCR (qRT-PCR); expression of CDSN by immunohistochemistry, qRT-PCR, and Western blot; and expressions of tissue kallikrein-related peptidase (KLK)5, KLK7, KLK14, and serine peptidase inhibitor Kazal type 5 (SPINK5) by qRT-PCR. RESULTS: TGase2 was higher (P=0.0046) and TGase5 was lower (P=0.0008) in cholesteatoma than in the postauricular skin. Immunoreactivity for isopeptide bonds was localized in the granular and horny layers, and was not different between the two tissues. Immunoreactivity for CDSN was localized in the granular layer, and was lower in cholesteatoma than in the skin (P=0.0090). Western blot and qRT-PCR confirmed that the expression of CDSN was lower in cholesteatoma than in the skin. Expressions of KLK5, KLK7, KLK14, or SPINK5 were not different between the two tissues. CONCLUSIONS: These results indicate that the production of CDSN is likely to be suppressed in cholesteatoma, which would account, at least in part, for the mechanical fragility and increased permeability of the cholesteatoma epithelium.

Relationship between copper and lipids and atherogenic indices soon after birth in Japanese preterm infants of 32-35 weeks.

Several studies have reported association of altered levels of lipids and some trace elements with risk factors for cardiovascular disease development in adulthood. Accordingly, the present study aimed to determine the relationship among the serum levels of copper (Cu), zinc (Zn), lipids, lipoproteins and apolipoproteins in preterm infants through an assessment of atherogenic indices shortly after birth. Blood samples were collected within 20 min of birth from 45 preterm infants with gestational ages ranging from 32 to 35 weeks. Serum Cu, Zn, total cholesterol (TC), low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc), apolipoprotein-A1 (apoA1) and apolipoprotein-B (apoB) levels were measured, and the TC/HDLc, LDLc/HDLc and apoB/apoA1 ratios were calculated. Upon determining the correlation between the levels of Cu, Zn and these indices of lipid metabolism, triglyceride (TG) and Cu were found to correlate negatively with birth weight (BW) and the standard deviation (s.d.) score for body weight. Furthermore, Cu levels correlated positively with the TG level and TC/HDLc, LDLc/HDLc and apoB/apoA1 ratios and negatively with the HDLc level and HDLc/apoA1 ratios. However, a stepwise multiple regression analysis indicated that the s.d. score for BW and TG level were significant independent determinants of the Cu level. In contrast, Zn did not correlate with any of these indices. In conclusion, intrauterine growth restriction and the TG level at birth influence Cu levels in preterm infants, whereas atherogenic indices do not affect this parameter.

Scoring system to predict hemorrhage in pelvic ring fracture.

BACKGROUND: Risk factors for hemorrhage in patients with pelvic ring fracture have been widely reported. Because there are many risk factors, it is thought that prediction accuracy of hemorrhage in cases of pelvic ring fracture could be improved by using a scoring system. HYPOTHESIS: We investigated the risk factors for massive hemorrhage (MH) and created a novel predictive score of MH in pelvic ring fractures. MATERIAL AND METHODS: We retrospectively reviewed patients with pelvic ring fractures (Abbreviated Injury Score≥3 and age≥16 years) from January 2007 to June 2015. We excluded the cases that might have hemorrhage from other sites sufficient to require a blood transfusion. Massive hemorrhage was defined as hemorrhage requiring transfusion of≥6 red cell concentrate units within 24h of admission. RESULTS: The MH group included 27 patients and the non-MH group included 71 patients. Lactate level, AO/OTA classification and extravasation of computed tomography (CT) contrast fluid had a significantly higher risk as a result of multivariable analysis. The combined score using these risk factors according to their odds-adjusted ratios was created to predict for MH: lactate level>2.5-5.0 (mmol/L)=1 point,>5.0 (mmol/L)=2 points, partially stable (OA/OTA classification B1/B2/B3)=1 point, unstable (C1/C2/C3)=2 points, pelvic extravasation of contrast on CT=4 points. The AUC of the calculated score was 0.93 (95% CI: 0.89-0.98). CONCLUSION: The combined score using these risk factors according to their odds-adjusted ratios was created to predict MH and was an effective prediction score. LEVEL OF EVIDENCE: IV, retrospective study.

Influence of gestational age on serum incretin levels in preterm infants.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the incretin hormones secreted from the intestine in response to enteral feeding to stimulate insulin secretion. We investigated the relationship serum GIP and GLP-1 levels with gestational age, and insulin secretion in preterm infants. Serum GIP and GLP-1 levels were measured at birth and at 1, 2 and 4 weeks after birth in 30 infants, including 12 born before 30th week of gestation (early group) and 18 born after 30th week of gestation (late group). Blood glucose and serum insulin levels were measured, and the quantitative insulin sensitivity check index (QUICKI) was also calculated. The levels of GLP-1 at 2 and 4 weeks were significantly higher in the early group than those in the late group. The levels of GIP were not significantly different between two groups. At 4 weeks, serum insulin level was significantly higher and QUICKI was significantly lower in the early group. Furthermore, GLP-1 levels were significantly correlated with QUICKI and the serum insulin levels in all infants at 4 weeks. In preterm infants, enteral feeding to premature intestine may be associated with GLP-1 secretion. GLP-1 is also related to stimulated insulin secretion in early postnatal period.

UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO.

The t(8;21) rearrangement, which creates the AML1-ETO fusion protein, represents the most common chromosomal translocation in acute myeloid leukemia (AML). Clinical data suggest that CBL mutations are a frequent event in t(8;21) AML, but the role of CBL in AML1-ETO-induced leukemia has not been investigated. In this study, we demonstrate that CBL mutations collaborate with AML1-ETO to expand human CD34+ cells both in vitro and in a xenograft model. CBL depletion by shRNA also promotes the growth of AML1-ETO cells, demonstrating the inhibitory function of endogenous CBL in t(8;21) AML. Mechanistically, loss of CBL function confers hyper-responsiveness to thrombopoietin and enhances STAT5/AKT/ERK/Src signaling in AML1-ETO cells. Interestingly, we found the protein tyrosine phosphatase UBASH3B/Sts-1, which is known to inhibit CBL function, is upregulated by AML1-ETO through transcriptional and miR-9-mediated regulation. UBASH3B/Sts-1 depletion induces an aberrant pattern of CBL phosphorylation and impairs proliferation in AML1-ETO cells. The growth inhibition caused by UBASH3B/Sts-1 depletion can be rescued by ectopic expression of CBL mutants, suggesting that UBASH3B/Sts-1 supports the growth of AML1-ETO cells partly through modulation of CBL function. Our study reveals a role of CBL in restricting myeloid proliferation of human AML1-ETO-induced leukemia, and identifies UBASH3B/Sts-1 as a potential target for pharmaceutical intervention.

Increased permeability of the epithelium of middle ear cholesteatoma.

OBJECTIVE: We investigated the electrical impedance of and the expressions of tight junction molecules in the cholesteatoma epithelium to provide supporting evidence for the acid lysis theory of bone resorption in middle ear cholesteatoma. METHODS: Study subjects were patients with primary acquired middle ear cholesteatoma and those with non-cholesteatomatous chronic otitis media who underwent tympanomastoidectomy. The electrical impedance of the cholesteatoma epithelium was measured during tympanomastoidectomy by loading alternating currents of 320 Hz and 30.7 kHz. The expressions of tricellulin (MARVELD2), claudin-1 (CLDN1) and claudin-3 (CLDN3) were examined by fluorescence immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. RESULTS: The electrical impedance of the cholesteatoma epithelium was significantly lower than that of the post-auricular skin and external auditory canal skin at both 320 Hz and 30.7 kHz. Immunoreactivity for MARVELD2, CLDN1 and CLDN3 was localised mainly in the granular layer, and to lesser degree, in the horny and spinous layers in both the cholesteatoma tissue and post-auricular skin. Fluorescence intensity was moderate for MARVELD2, weak for CLDN1 and strong for CLDN3. The expressions of MARVELD2, CLDN1 and CLDN3 mRNA were significantly lower in the cholesteatoma tissue than in the post-auricular skin. CONCLUSIONS: These results indicate the increased permeability of the cholesteatoma epithelium and suggest that this change is, at least partially, dependent on the decrease in the expressions of the tight junction molecules. This evidence supports the acid lysis hypothesis of bone resorption in cholesteatoma.

SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS.

Mutations in ASXL1 are frequent in patients with myelodysplastic syndrome (MDS) and are associated with adverse survival, yet the molecular pathogenesis of ASXL1 mutations (ASXL1-MT) is not fully understood. Recently, it has been found that deletion of Asxl1 or expression of C-terminal-truncating ASXL1-MTs inhibit myeloid differentiation and induce MDS-like disease in mice. Here, we find that SET-binding protein 1 (SETBP1) mutations (SETBP1-MT) are enriched among ASXL1-mutated MDS patients and associated with increased incidence of leukemic transformation, as well as shorter survival, suggesting that SETBP1-MT play a critical role in leukemic transformation of MDS. We identify that SETBP1-MT inhibit ubiquitination and subsequent degradation of SETBP1, resulting in increased expression. Expression of SETBP1-MT, in turn, inhibited protein phosphatase 2A activity, leading to Akt activation and enhanced expression of posterior Hoxa genes in ASXL1-mutant cells. Biologically, SETBP1-MT augmented ASXL1-MT-induced differentiation block, inhibited apoptosis and enhanced myeloid colony output. SETBP1-MT collaborated with ASXL1-MT in inducing acute myeloid leukemia in vivo. The combination of ASXL1-MT and SETBP1-MT activated a stem cell signature and repressed the tumor growth factor-ß signaling pathway, in contrast to the ASXL1-MT-induced MDS model. These data reveal that SETBP1-MT are critical drivers of ASXL1-mutated MDS and identify several deregulated pathways as potential therapeutic targets in high-risk MDS.

Hypothalamic ATF3 is involved in regulating glucose and energy metabolism in mice.

AIMS/HYPOTHESIS: The pancreas and hypothalamus are critical for maintaining nutrient and energy homeostasis, and combined disorders in these organs account for the onset of the metabolic syndrome. Activating transcription factor 3 (ATF3) is an adaptive response transcription factor. The physiological role of ATF3 in the pancreas has been controversial, and its role in the hypothalamus remains unknown. To elucidate the roles of ATF3 in these organs, we generated pancreas- and hypothalamus-specific Atf3 knockout (PHT-Atf3-KO) mice in this study. METHODS: We crossed mice bearing floxed Atf3 alleles with Pdx1-cre mice, in which cre is specifically expressed in the pancreas and hypothalamus, and analysed metabolic variables, pancreatic morphology, food intake, energy expenditure and sympathetic activity in adipose tissue. We also used a hypothalamic cell line to investigate the molecular mechanism by which ATF3 regulates transcription of the gene encoding agouti-related protein (Agrp). RESULTS: Although PHT-Atf3-KO mice displayed better glucose tolerance, neither plasma glucagon nor insulin level was altered in these mice. However, these mice exhibited higher insulin sensitivity, which was accompanied by a leaner phenotype due to decreased food intake and increased energy expenditure. We also observed decreased hypothalamic Agrp expression in PHT-Atf3-KO mice. Importantly, an increase in ATF3 levels is induced by fasting or low glucose in the hypothalamus. We also showed that ATF3 interacts with forkhead box-containing protein, O subfamily 1 (FoxO1) on the Agrp promoter and activates Agrp transcription. CONCLUSIONS/INTERPRETATION: Our results suggest that ATF3 plays an important role in the control of glucose and energy metabolism by regulating Agrp.

Tunable terahertz emission from the intrinsic Josephson junctions in acute isosceles triangular Bi2Sr2CaCu2O8+δ mesas.

In order to determine if the mesa geometry might affect the properties of the coherent terahertz (THz) radiation emitted from the intrinsic Josephson junctions in mesas constructed from single crystals of the high-temperature superconductor, Bi2Sr2CaCu2O8+δ, we studied triangular mesas. For equilateral triangular mesas, the observed emission was found to be limited to the single mesa TM(1,0) mode. However, tunable radiation over the range from 0.495 to 0.934 THz was found to arise from an acute isosceles triangular mesa. This 47% tunability is the widest yet observed from the outer current-voltage characteristic branch of such mesas of any geometry. Although the radiation at a few of the frequencies in the tunable range appear to have been enhanced by cavity resonances, most frequencies are far from such resonance frequencies, and can only be attributed to the ac-Josephson effect.

First-principles study of nanometer-sharp domain walls in ferromagnetic Fe monolayers under in-plane strain.

We investigated a nanometer-sharp magnetic domain wall (DW) structure in a free-standing Fe(110) monolayer and studied the crucial role of in-plane strain using fully unconstrained noncollinear ab initio spin-density-functional theory calculations within the generalized gradient approximation. The DW width is calculated to be 0.86 nm. A precise vector-field description of the magnetization density revealed that a noncollinear character in the DW was spatially confined between atoms, whereas a collinear and high magnetization density was localized around each atom. In the rapid rotation of magnetic moments in the DW, we found an electron rearrangement from the d(zx) and d(x(2)-y(2)) states to the d(xy), d(yz) and d(z(2)) states due to a shift of band structures. Applied tensile and compressive in-plane strains both bring about narrower DWs in the monolayer except when the strain is small. The strain dependence of the DW width is discussed in terms of both exchange interaction and magnetocrystalline anisotropy.

Local suppression of ferroelectricity at PbTiO3 surface steps: a density functional theory study.

Ab initio (first-principles) density functional theory (DFT) calculations are performed within the local density approximations (LDA) to investigate the ferroelectricity at PbTiO(3) surface steps consisting of (001) and (100) surfaces with a spontaneous polarization along [100]. For both the PbO- and TiO(2)-terminated surface steps, the [100] polarization is suppressed and the [001] polarization appears at their upper terraces, which results in a rotation of polarizations at the surface steps. The polarization rotation is induced by the local variation of the covalent Pb-O bond due to the charge redistribution at the surface steps. Furthermore, we investigate the interaction of the surface steps. Although surface steps with the same polarization configuration exhibit little interaction, steps of different types interact with each other strongly, suppressing the ferroelectricity, especially on the upper terrace.

Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis.

Ras guanyl nucleotide-releasing proteins (RasGRPs) are activators of Ras. Previous studies have indicated the possible involvement of RasGRP1 and RasGRP4 in leukemogenesis. Here, the predominant role of RasGRP1 in T-cell leukemogenesis is clarified. Notably, increased expression of RasGRP1, but not RasGRP4, was frequently observed in human T-cell malignancies. In a mouse bone marrow transplantation model, RasGRP1 exclusively induced T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) after a shorter latency when compared with RasGRP4. Accordingly, Ba/F3 cells transduced with RasGRP1 survived longer under growth factor withdrawal or phorbol ester stimulation than those transduced with RasGRP4, presumably due to the efficient activation of Ras. Intriguingly, NOTCH1 mutations resulting in a gain of function were found in 77% of the RasGRP1-mediated mouse T-ALL samples. In addition, gain-of-function NOTCH1 mutation was found in human T-cell malignancy with elevated expression of RasGRP1. Importantly, RasGRP1 and NOTCH1 signaling cooperated in the progression of T-ALL in the murine model. The leukemogenic advantage of RasGRP1 over RasGRP4 was attenuated by the disruption of a protein kinase C phosphorylation site (RasGRP1(Thr184)) not present on RasGRP4. In conclusion, cooperation between aberrant expression of RasGRP1, a strong activator of Ras, and secondary gain-of-function mutations of NOTCH1 have an important role in T-cell leukemogenesis.