Influence of parent age and gender on anticipation in familial B-cell malignancies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7553-7553
Author(s):  
D. T. Alexandrescu ◽  
K. Brown ◽  
J. P. Dutcher ◽  
P. H. Wiernik
Keyword(s):  
B Cell ◽  
Genetic Basis ◽  
Hematological Malignancies ◽  
Pearson Correlation ◽  
Mean Difference ◽  
B Cell Malignancies ◽  
Significant Difference ◽  
Familial Hematological Malignancies ◽  
And Gender ◽  
All Diseases

7553 Background: Anticipation (A) occurs when a disease manifests at an earlier age or with increased severity in the next generation. Dependence of A on parent age and sex has not been previously investigated in B-cell malignancies. Methods: 144 pairs [45 mixed Hodgkin’s/non-Hodgkin’s (HD/NHL) and NHL/HD, 44 NHL, 24 HD and 31 CLL] were analyzed retrospectively for presence of anticipation in overall, paternal (PT) and maternal transmission (MT). 90 pairs belong to our familial hematological malignancies database, and 54 were pooled from the literature. A among diseases, as well as PT and MT were compared by t-test. Parent age at conception was correlated with A by Pearson correlation (PC). Results: Age at conception was similar among all malignancies, and overall anticipation varied between −18.93 and −26.61 yr, with no significant difference among diseases, except between CLL and mixed HD/NHL-NHL/HD (−18.93 vs. −26.61 yr, mean difference −7.68 yr, p = 0.03, 95% CI −14.74 to −0.62). A significant PC between the parent age at conception and A was found for all malignancies, with the exception of borderline significance in the case of mixed HD/NHL-NHL/HD MT. No difference in overall A was observed between PT and MT, except for HD (−27.25 vs. −14.25 yr, mean difference −13.00 years, P = 0.02, 95% CI −23.68 to −2.32). However, higher PCs were observed with PT than MT for all diseases (Table). Conclusions: A is present in all familial B-cell malignancies analyzed and it correlates with parent age of conception. Although mean absolute A was more prominent with PT than MT only in the case of HD, all diseases showed a tendency towards a higher PC with PT. Although less prominent than with neurological disease, this phenomenon points towards a germline inheritance of B-cell malignancies and a common genetic basis for HD and NHL. [Table: see text] No significant financial relationships to disclose.

Analysis of BCL11A gene Variants in Hematological Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2956-2956
Author(s):  
Maria Monne ◽  
Giovanna Piras ◽  
Antonella Uras ◽  
Marco Murineddu ◽  
Angelo D. Palmas ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Hematological Malignancies ◽  
Lymphoblastic Leukemia ◽  
Myeloproliferative Disorders ◽  
P Value ◽  
T Cell Lymphomas ◽  
Genotype Frequencies ◽  
Increased Risk ◽  
Significant Difference

Abstract Abstract 2956 Poster Board II-932 Background. The B-cell leukemia 11A gene (BCL11A/Evi9/CTIP1) is essential for normal lymphoid development and genetic association studies have shown its potential regulator effect in blood related phenotypes. BCL11A encodes a Krüppel-like zinc-finger protein and functions as a transcriptional repressor through its interaction with several proteins including BCL6. The corresponding mouse gene is a common site of retroviral integration in myeloid leukemia, and may function as a leukemia oncogene. It is down-regulated during hematopoietic cell differentiation and abnormalities involving this gene have been detected in a variety of B-cell malignancies in humans. We genotyped SNP rs11886868 in the BCL11A gene, which has been previously associated with HbF production, in patients with hematological malignancies from Sardinia to investigate a possible contribution of this gene in determining genetic susceptibility to onco-hematological diseases. Patients and Methods. We screened a total of 325 patients with hematological malignancies for rs11886868 SNP at the BCL11A locus using the TaqMan allelic discrimination assay: 51 B-cell Non Hodgkin's lymphoma (NHL), 27 Hodgkin's disease (HD), 42 Chronic Lymphocytic Leukemia (CLL), 52 Multiple Myeloma, 35 Cutaneous T-cell Lymphomas (CTCL), 11 Acute Lymphoblastic Leukemia (ALL), 19 Myelodysplastic Syndromes (MDS), 31 Acute Non Lymphoblastic Leukemia (ANLL), 36 Philadelphia negative Myeloproliferative Disorders (MPD), 21 Chronic Myelogenous Leukemia. Fifty–four DNAs from healthy individuals were used as population controls. Both patients and controls originated from central Sardinia. The frequencies comparisons between controls and cases were performed using chi-square test and Odds Ratio (OR) analysis with Cornfield 95% confidence intervals (CI). Results. Allele frequencies for BCL11A rs11886868 were 22% for the “C” allele and 78% for the “T” allele. No statistically significant difference was observed between cases and controls. All genotypes were in Hardy-Weinberg equilibrium for both patients and controls groups. The genotype frequencies were 65% (T/T), 26% (C/T) and 9% (C/C) in controls and 53% (T/T), 40.5% (C/T), and 6.5% (C/C) in hematological malignancies. When compared with the genotype frequencies reported for Caucasian and healthy controls from Sardinia no statistically significant difference was observed (p=0.4). However, the C/T genotype was more frequent in cases than controls (41% vs 26%) conferring an increased risk for hematological malignancies with an estimated OR=1,9 (95%CI 1.08-3.6; p=0.03). In detail, statistically significant differences in genotype distribution were observed in CTCL (p< 0.0001), MPD (p=0.0006), NHL (p=0.008), HD (p=0.002) and ALL patients (p=0.02). The C/C genotype was not observed in CTCL and HD patients, while heterozygousity conferred an increased risk of 4.2 (2.3-7.7; p value <0.0001) and 2.6 (1.6-4.7; p value <0.002), respectively. The C/T genotype was also overrepresented in MPD with an estimated OR of 3.2 (1.7-5.8; p value= 0.0001) and NHL with OR of 2.7 (1.5-4.9; p value <0.001). Stratification for clinical and biological parameters showed that among CLLs, the C/C genotype was present in 4/27 (15%) of the CD38-negative patients and in none of the CD38-positive subgroup. By contrast, the homozygousity for the ancestral “T” allele was not observed in Mantle Cell and Marginal Zone Lymphomas. Conclusions. We found genetic association of BCL11A gene in several blood disorders with the strongest association for Cutaneous T-cell Lymphomas and Myeloproliferative disorders suggesting a possible role of BCL11A in both lymphoid and myeloid lineages. Specific BCL11A genotypes have been associated with different BCL11A expression levels that influence HbF production. We speculate that BCL11A sequence variants may influence expression of different isoforms that may have effect on cell pathways involved in oncogenetic events as well as in globin gene regulation. This work was supported by Associazione Italiana contro le Leucemie e Linfomi (AIL) Disclosures: No relevant conflicts of interest to declare.

Overexpression of BCL9, a Wnt/β-Catenin Transcriptional Co-Activator, in Transgenic Mice Promotes Spontaneous Development of B-Cell Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 441-441
Author(s):  
Tomasz Sewastianik ◽  
Jianjun Zhao ◽  
Meng Jiang ◽  
Peter S. Dennis ◽  
Myles Brown ◽  
...  
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
Signaling Pathway ◽  
Transcriptional Activity ◽  
Hematological Malignancies ◽  
B Cell Malignancies ◽  
Human Cancers ◽  
Stop Cassette

Abstract Dysregulation of the Wnt signaling pathway underlies the pathogenesis of a wide range of human cancers, including hematological malignancies such as multiple myeloma (MM). The terminal effector of this signaling pathway is a transcriptional complex formed by β-catenin and BCL9. This complex is of particular interest because the BCL9 locus resides on the frequently recurring 1q21 chromosomal amplification in MM, which has been linked to poor clinical prognosis and outcome. Our previous studies indicate that BCL9-mediated enhancement of β-catenin activity increases cells proliferation, migration, invasion, and the metastatic potential of MM cells. Therefore, in order to: (I) unequivocally determine the oncogenic role of BCL9, (II) better understand its mechanism of action, and (III) develop mouse preclinical model of cancer with dysregulated Wnt/β-catenin/BCL9 activity, we generated transgenic mouse models. To overcome problems inherently related to embryonic lethality, we generated BCL9fl/- conditional transgenic mice using site-specific transgene integration into the mouse ColA1 gene in embryonic stem cells. To remove the stop cassette and activate BCL9 expression in vivo, we generated AID-Cre+/-; BCL9fl/- and ERT2-Cre+/-; BCL9fl/- compound mice. Recombinase activity driven by AID (activation-induced cytidine deaminase) gene promoter or ER receptor after tamoxifen administration, caused removal of the stop cassette and expression of BCL9 in germinal center (GC) B cells or several tissues, respectively, as confirmed by immunoblot, immunohistochemical (IHC) and PCR analysis. Since BCL9 is a β-catenin co-activator, next we generated cohorts of AID-Cre+/-; BCL9fl/-; TCF/Lef1-lacZ+/- and ERT2-Cre+/-; BCL9fl/-; TCF/Lef1-lacZ+/- triple compound transgenic mice carrying the Wnt reporter system that expresses β-galactosidase (β-gal), to determine whether Wnt/β-catenin transcriptional activity is increased as a consequence of BCL9 overexpression in vivo. β-gal stain was increased in frequency and intensity in cells within GCs but not outside them in AID-Cre+/-; BCL9fl/-; TCF/Lef1-lacZ+/- compared to control mice. In ERT2-Cre+/-; BCL9fl/-; TCF/Lef1-lacZ+/- mice β-gal staining was primarily detected in cells outside the GCs, not within them. Overall, these results indicate that Wnt transcriptional activity is increased in B-cells as a consequence of Cre-induced expression of BCL9 and that AID-Cre+/- and ERT2-Cre+/- target expression of BCL9 to GC and non-GC B cells, respectively. Because BCL9 is involved in the pathogenesis of human cancers, we evaluated whether our transgenic mice develop hematological malignancies. Except for mild splenic enlargement, BCL9-transgenic mice were indistinguishable from control mice between 8 and 30 weeks of age as assessed by weight and posture. However, after 40 weeks of age and at variable times thereafter, 80% (32/40) of AID-Cre+/-; BCL9fl/- and 70% (28/40) of ERT2-Cre+/-; BCL9fl/- mice but none from control cohorts showed signs of disease. Gross pathologic examination of euthanized animals with BCL9 overexpression revealed enlargement of the spleen and LNs. Two distinct patterns of clonal hematological malignancies were identified after detailed histological, IHC and molecular examination. In AID-Cre+/-; BCL9fl/- mice tumors resembled human plasmacytomas (PCs), whereas in ERT2-Cre+/-; BCL9fl/- mice B-cell acute lymphoblastic leukemia (B-ALL). This later result is of particular interest, since BCL9 was first identified by cloning the t(1;14)(q21;q32) translocation from a patient with B-ALL. These findings indicate that BCL9 overexpression at different stages of B-cell development leads to distinct subtypes of B-cell malignancies. Finally, we investigated the BCL9 expression in human extramedullary plasmocytomas (EMP) and B-ALL. 32% of EMP cases analyzed by IHC expressed BCL9 at significant levels. Utilizing gene expression data available in the public domain we also showed that BCL9 is significantly overexpressed in ETV6-RUNX1 and TCF3-PBX1 subtypes of human B-ALL when compared to normal bone marrow counterparts, suggesting that BCL9 may play important roles in the pathogenesis of EMP as well as B-ALL in humans. Since BCL9 is highly expressed in tumors but not in the cells of origin and its interaction with β-catenin is specific, these results imply BCL9 as a promising candidate for targeted therapy. Disclosures No relevant conflicts of interest to declare.

The influence of parental age and gender on anticipation in familial B-Cell malignancies

2007 ◽  
Vol 24 (1) ◽  
pp. 55-62 ◽  
Author(s):  
Doru T. Alexandrescu ◽  
Peter H. Wiernik
Keyword(s):  
B Cell ◽  
Parental Age ◽  
B Cell Malignancies ◽  
Age And Gender ◽  
And Gender

scholarly journals Anatomical Course Demarcating the Safe Area for the Superior Gluteal Nerve

2020 ◽  
Vol 12 (2) ◽  
Author(s):  
Simon Lammy
Keyword(s):  
Health Care Professionals ◽  
Iliac Crest ◽  
Pearson Correlation ◽  
Greater Trochanter ◽  
Superior Gluteal Nerve ◽  
Surface Anatomy ◽  
Bony Surface ◽  
Safe Area ◽  
Significant Difference ◽  
And Gender

Iatrogenic injury to the superior gluteal nerve (SGN) persists despite a safe area being defined. Current descriptions of the course of the SGN are conflicting and do not provide agreeable distances to surface landmarks that are useful for most health care professionals. This study aimed to suggest a more conservative and gender-dependent estimate of the safe area between each buttock and genitals as defined by four bony surface landmarks. The posterior and lateral surfaces of each buttock in eight cadavers, four male and four female, were dissected. The surface anatomy of sixteen SGNs was defined in relation to the quadrate tubercle of the intertronchanteric crest of the femur (QTIF), the most cranial ridge of the iliac crest (IC), the anterior superior iliac spine (ASIS) and the posterior superior iliac spine (PSIS). Between the sexes, no significant difference existed concerning average SGN lengths across each buttock pair, (i.e. SGN length male/female difference df=3 (p=0.273); Pearson = - 0.76). There was no significant difference between both buttock sides concerning the SGN distances from each of the four bony surface landmarks across either sex (e.g. male QTIF df=3 (p=0.284); Pearson correlation = -0.31.) From our measurements we conclude that the standard safe area is too generous and should be half the size immediately adjacent to the tip of the greater trochanter.

scholarly journals The Effects of University Students’ School Climate on Their Motivation Levels

2021 ◽  
Vol 8 (2) ◽  
pp. 112-121
Author(s):  
Okan BİLGİN
Keyword(s):  
School Climate ◽  
University Students ◽  
Pearson Correlation ◽  
Analysis Technique ◽  
Significant Difference ◽  
Dimensions Of Learning ◽  
Adult Motivation ◽  
Climate Scale ◽  
And Gender ◽  
The Relationship

The present study aims to investigate the relationship between university students' school climate and their motivation levels. In this study, whether the school climate and motivation levels differ according to gender and year of study also been examined. The "School Climate Scale for University Students" and "Adult Motivation Scale" were applied to 322 participants aged between 18 and 40. Correlational survey model was used in this study. Pearson correlation coefficient was examined to investigate the relationship between school climate and motivation. The effects of university students' school climate on motivation were analyzed using the regression analysis technique. T-test and one-way analysis of variance technique were used to investigate whether the school climate and motivation differed according to gender and year of study. The findings showed that there was no significant difference between university students' school climate and motivation levels and gender. According to the other variable, the year of study, a significant difference was found in the dimensions of learning environment and communication, which were sub-dimensions of school climate. When the relationship between school climate and motivation levels of university students was examined, the findings showed that there was a positive significant relationship between school climate and its sub-dimensions and motivation and sub-dimensions.

scholarly journals Combined Loss of Tet1 and Tet2 Promotes B-Cell, but Not Myeloid Malignancies in Mice

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3650-3650
Author(s):  
Zhigang Zhao ◽  
Lin Li ◽  
Meelad Dawlaty ◽  
Feng Pan ◽  
Zhe Li ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Cultures ◽  
High Throughput ◽  
High Throughput Sequencing ◽  
Hematological Malignancies ◽  
Cell Populations ◽  
Double Knockout ◽  
B Cell Malignancies ◽  
Myeloid Malignancies ◽  
Genome Wide

Abstract Objective: Tet1/2/3 are methylcytosine dioxygenases regulating cytosine methylation in the genome. Tet1 and Tet2 are abundantly expressed in HSC/HPCs and implicated in hematological malignancies. Tet2 -deletion in mice causes myeloid malignancies, while Tet1 -null mice are overtly normal early in life. Here, we investigated the overlapping and non-redundant functions of Tet1/Tet2 in HSC maintenance and hematological malignancies using Tet1/2 double knockout (DKO) mice. Methods: 1) Kinetic analysis of the hematologicalparameters on WT, Tet1-/-, Tet2-/- and DKO mice; 2) Analysis of HSC, myeloid and lymphoid progenitors and various maturation stages of B-cell populations; 3) Competitive bone marrow reconstitution assay; 4) RAN-Seq on LK cells and B220+ cells from young/undiseased and diseased DKO mice respectively; 5) Chemical labeling and affinity purification method coupled with high-throughput sequencing (hMe-Seal) to profile the genome-wide distribution of 5hmC, and methylated DNA immunoprecipitation coupled with high-throughput sequencing (MeDIP-seq) to profile 5mC in BM LK cells from young WT, Tet2-/- and DKO mice; 6) q-PCR analysis of the mRNA expression levels of Tet1 and Tet2 on BM CD19+ cells from B-ALL patients and compared to that of CD19+ B-cells from healthy controls. Results: We found that T et 1 and T et 2 are often concomitantly down-regulatedin patients with B-ALL. Therefore, it is important to investigate the effects of combined loss of Tet1 and Tet2 on the hematopoietic phenotype and development of hematological malignancies in vivo. The LSK and CMP/GMP/MEP cell populations are comparable in yound WT, Tet1-/- and DKO mice, while were significantly increasedin Tet2-/- mice. When a replating assay was performed using LSK cells, Tet2-/- LSK cell cultures had a significant higher colony formation in each round of replating, while Tet1-/- and DKO LSK cell cultures only exhibited a moderate increase in the number of colonies at P2, but not P3 and P4. Furthermore, young DKO mice had an increased percentage of CLP, BLP and Pro-/Pre-/Immature-B cell populations in their BM as compared to WT, Tet1-/- and Tet2-/- mice. Consistent to the B-lineage phenotypic analysis, DKO BM cells contained higher pre-B cell colony forming cells than the three genotypes of control mice. Interestingly, DKO mice exhibited a strikingly decreased incidence and delayed onset of myeloid malignancies compared to Tet2-/- mice and in contrast developed lethal B-cell malignancies, most closely resembling B-ALL. The loss of Tet2 or DKO leads to genome-wide alterations of both 5mC and 5hmC. Significant overlaps between the differential hydroxymethylated regions (DhMRs) or differential methylated regions (DMRs) of two genotypes of LK cells were observed. However, intriguingly, the overlaps between DhMRs and DMRs within each genotype of LK cells were minimal, indicating that DhMRs and DMRs might represent distinct loci with altered epigenetic modifications under these conditions. When the expression of a pool of 654 genes that are known to be involved in regulating hematopoietic cell development and/or promoting leukemogenesis were overlap with DhMRs and DMRs identified above, we observed significant numbers of these genes with altered either 5hmC or 5mC modifications which however did not alter their gene expression. Furthermore, RNA-Seq on B-ALL DKO B220+ cells showed alteration of a set of genes involved in B-cell development and B-cell lymphoma/leukemogenesis. Conclusion: Using Tet1/2 double knockout mice, we found that Tet1 is required for Tet2 -deletion mediated HSC dysregulation, myeloid skewing and myeloid malignancy, indicating distinct roles of the two enzymes. Tet1 loss modulates the Tet2 -deletion mediated disease phenotype, not only decreasing the incidence and delaying the onset of myeloid malignancies, but also promoting the pathogenesis of B-cell malignancies. Furthermore, our observations highlight the roles of distinct cytosine modifications, particularly 5hmC, could play in marking the specific genes and enabling cells to fate decision change upon stimulation signals. These findings provide a pathological framework for further elucidating the molecular mechanisms and critical cross talks between Tet1 and Tet2 in the pathogenesis of hematological malignancies. Disclosures No relevant conflicts of interest to declare.

Important Role of B2-Glycoprotien in Females with Recurrence Abortion

2018 ◽  
Vol 9 (01) ◽  
Author(s):  
Ahmed Abbas Hasan ◽  
Radhia Hussain Fadel ◽  
Saeed Hilal Khudhair ◽  
Doaa Hashim Jawad
Keyword(s):  
Pearson Correlation ◽  
Mean Value ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
P Value ◽  
Recurrent Abortion ◽  
Significant Difference ◽  
Medical City ◽  
And Gender ◽  
Age Range

Recurrent abortion consider as one of the most common problem in world. There are different causes associated with recurrent abortion, these may be occur due to complication of microorganism infection or associated with immunological disturbance like abortion caused by Anti-phospholipid syndrome, or associated with SLE. The anti-b2glucoprotien antibodies have a role in abortion. In this study, we wish to determine whether there is a relationship between the levels of these anti-b2glucoprotien antibodies and abortion. Thirty females patients with spontaneous abortion (10 of them with Antiphospholipid syndrome,10 of them with systemic lupus erthymatosus and final 10 with toxoplasmosis with ages ranged between (20-46) where taken from (Al-Hussein Medical City/Kerbala). Control group consisted of 20 healthy people who were free from history of abortion who matched in age and gender with patients. B2gp(IgMandIgG) EASIA Kit, generic assay) and was studied using the enzyme-linked immunosorbent assay (ELISA) method. T-test and ANOVA and Pearson correlation used to analyze results by using SPSS version 24. P-value ≤ 0.05 was considered significant. The patients with age range blow 30 years show high percent(63.3%) among the other groups .most of the patients have high percent of 3 times abortion were reported in all different groups .The mean value of anti-B2gP-I IgG (45.354) show highly a significant difference results in aborted patients with APS and significant difference in patients with SLE when compared with controls groups. the Anti-B2gPI IgM not give statistically significant difference when camper to health cases. we conclude that the Anti-B2GPI IgG levels were increased significantly in aborted females with APS and SLE .

Inhibition Of PI3K-δ and -γ Isoforms By IPI-145 In Chronic Lymphocytic Leukemia Overcomes Signals From PI3K/AKT/S6 Pathway and Promotes Apoptosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4167-4167 ◽  
Author(s):  
Kumudha Balakrishnan ◽  
Marisa Peluso ◽  
Min Fu ◽  
Nathalie Y. Rosin ◽  
Jan A. Burger ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Research Funding ◽  
Therapeutic Potential ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Employment Equity ◽  
Enhanced Production ◽  
Significant Difference ◽  
Equity Ownership

Abstract The functional relevance of the B cell Receptor (BCR) pathway and identification of protein kinases as therapeutic targets have recently shifted the paradigm for treatment of B cell malignancies. Inhibition of protein and lipid kinases (Bruton Tyrosine Kinase [BTK] and phosphoinositide 3-kinase [PI3K]) with ibrutinib and GS-1101 has been shown to be active in treatment of chronic lymphocytic leukemia (CLL). Importantly, differential expression and function of PI3K isoforms support isoform-selective inhibition of this kinase in CLL. Whilst PI3K-α and PI3K-β are ubiquitously expressed, PI3K-δ and PI3K-γ are primarily restricted to leukocytes. Since CLL cells generally express high levels of active PI3K-δ, great interest has been focused on inhibition of PI3K-δ. However, given the distinct and non-overlapping roles of PI3K-δ and PI3K-γ in immune cells, exploration of the therapeutic potential of combined inhibition of both PI3K-δ and PI3K-γ in CLL patients is warranted. IPI-145 is a potent, orally bioavailable, inhibitor of PI3K-δ and PI3K-γ isoforms with KD values of 0.023 nM and 0.24 nM, respectively. Treatment of primary CLL cells (n=51) with IPI-145 (1 µM) resulted in significant apoptosis (median 33%; range 12 – 40%). Patients with mutated (n=13) or unmutated IGHV gene status (n=13), previously untreated (n=21) or treated (n=8), displayed no significant difference in apoptosis from IPI-145. Samples with different prognostic markers such as 13q (del) or FISH negative samples were equally sensitive to IPI-145. Side by side studies of IPI-145 with ibrutinib and GS-1101, revealed that IPI-145 is comparatively potent (IC50 7.6 µM, compared to >10 µM) in promoting apoptosis. Crosslinking with anti-IgM enhanced the survival of primary CLL cells in association with activation of PI3K-δ,γ/AKTSer473/pBadSer136/S6Ser235/236 pathway, which was in turn mitigated upon treatment with IPI-145 (n=9). Consistent with cell death, cleavage of PARP and decrease in anti-apoptotic protein Mcl-1 (but not Bcl-2 or Bcl-xL) was observed. Measurement of the C-C chemokine, CCL3, a biomarker for BCR signaling inhibition in CLL, demonstrated 15 to 48 – fold increase upon anti-IgM stimulation, which was reversed when cells were treated with 1 µM IPI-145 (10 to 80-fold decrease; n=6). Alternatively, co-culturing CLL primary cells with bone marrow stromal cells to mimic the leukemic microenvironment induced the protein levels of all four Class I PI3K isoforms and downstream PI3K/AKT/S6 signaling axis, which was significantly attenuated by IPI-145. To mimic the proliferative state in lymph node pseudofollicles, CLL cells were stimulated to proliferate with CD40L/IL-2/IL-10 and the effect of IPI-145 was measured. Both pAKT and Ki-67 expression were markedly inhibited in primary CLL cells at concentrations of IPI-145 in the low nanomolar range (EC50<10nM; n=2), suggesting a potent anti-proliferative effect of IPI-145 on CLL cells in the nodal environment. Given the significant role of the chemo-attractant, SDF-1, in the directed migration of B-cells, chemotaxis assay demonstrated reduction in migration of CLL cells towards SDF-1 in presence of IPI-145 (% control reduction - median 23%; range 2-42%; n=8). Furthermore, IPI-145 treatment enhanced production of reactive oxygen species (n=6). Taken together, these results demonstrate the potential of combined inhibition of the PI3K-δ and -γ isoforms in CLL, and support clinical investigation of IPI-145 in B-cell malignancies, including CLL. Disclosures: Balakrishnan: Infinity Pharmaceuticals Inc: Research Funding. Peluso:Infinity Pharmaceuticals., Inc.: Employment, Equity Ownership. Faia:Infinity Pharmaceuticals., Inc.: Employment, Equity Ownership. Kutok:Infinity Pharmaceuticals., Inc.: Employment, Equity Ownership. McGovern:Infinity Pharmaceuticals., Inc.: Employment, Equity Ownership. Gandhi:Infinity Pharmaceuticals., Inc: Research Funding.

scholarly journals Analysis of 153 115 patients with hematological malignancies refines the spectrum of familial risk

Blood ◽  
2019 ◽  
Vol 134 (12) ◽  
pp. 960-969 ◽  
Author(s):  
Amit Sud ◽  
Subhayan Chattopadhyay ◽  
Hauke Thomsen ◽  
Kristina Sundquist ◽  
Jan Sundquist ◽  
...  
Keyword(s):  
Relative Risk ◽  
B Cell ◽  
Hematological Malignancies ◽  
Hematological Malignancy ◽  
Familial Risk ◽  
B Cell Malignancies ◽  
Familial Relative Risk

Abstract Sud and colleagues interrogated the familial risk of hematological malignancy in association with over 150 000 patients. The majority of hematological malignancies showed increased familial relative risk, most prominently in association with B-cell malignancies.

scholarly journals Epigenomic translocation of H3K4me3 broad domains over oncogenes following hijacking of super-enhancers

2021 ◽  
pp. gr.276042.121
Author(s):  
Aneta Mikulasova ◽  
Daniel Kent ◽  
Marco Trevisan-Herraz ◽  
Nefeli Karataraki ◽  
Kent T.M Fung ◽  
...  
Keyword(s):  
B Cell ◽  
Hematological Malignancies ◽  
Chromatin Accessibility ◽  
Chromosomal Translocations ◽  
B Cell Malignancies ◽  
Super Enhancer ◽  
Its Gene ◽  
Breakpoint Detection ◽  
Broad Domain ◽  
T Cell Malignancies

Chromosomal translocations are important drivers of hematological malignancies whereby proto-oncogenes are activated by juxtaposition with super-enhancers, often called enhancer hijacking. We analysed the epigenomic consequences of rearrangements between the super-enhancers of the immunoglobulin heavy locus (IGH) and proto-oncogene CCND1 that are common in B cell malignancies. By integrating BLUEPRINT epigenomic data with DNA breakpoint detection, we characterised the normal chromatin landscape of the human IGH locus and its dynamics after pathological genomic rearrangement. We detected an H3K4me3 broad domain (BD) within the IGH locus of healthy B cells that was absent in samples with IGH-CCND1 translocations. The appearance of H3K4me3-BD over CCND1 in the latter was associated with overexpression and extensive chromatin accessibility of its gene body. We observed similar cancer-specific H3K4me3-BDs associated with super-enhancer hijacking of other common oncogenes in B cell (MAF, MYC and FGFR3/NSD2) and in T-cell malignancies (LMO2, TLX3 and TAL1). Our analysis suggests that H3K4me3-BDs can be created by super-enhancers and supports the new concept of epigenomic translocation, where the relocation of H3K4me3-BDs from cell identity genes to oncogenes accompanies the translocation of super-enhancers.

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