P–154 The role of the X Chromosome in early human embryo metabolism

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
A Groff ◽  
A Korkidakis ◽  
D Sakkas ◽  
D Page
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Electron Transport ◽  
X Chromosome ◽  
Early Embryo ◽  
P Value ◽  
Chromosome X ◽  
Embryo Metabolism ◽  
Early Human

Abstract Study question What role does the X chromosome play in early embryo metabolism? Does X chromosome copy number contribute to sex differences in early embryonic metabolism? Summary answer Chromosome X contains several metabolism-related genes that are expressed prior to X-inactivation, suggesting that their dosage plays a role in sex-biased regulation of embryo metabolism. What is known already Published reports indicate that sex differences in preimplantation embryo metabolism exist across mammalian species, including humans. Two observations supporting this are that male embryos reach blastocyst stage earlier than their female counterparts, and that glucose uptake and processing is thought to be higher in female compared to male embryos. It has been hypothesized that these differences reflect the location of the metabolism gene G6PD, the rate limiting enzyme in the Pentose Phosphate Pathway, on Chromosome X. Study design, size, duration This study is a reanalysis of publicly available RNA-seq data, including 1176 single cells from 59 blastocysts (24 E5, 18 E6, 17 E7) published in one study (Petropoulos et al 2016). Participants/materials, setting, methods Cells were subjected to a digital karyotype inference algorithm and aneuploid samples were removed from the dataset. Sex differential gene expression analyses (DE) were then performed in euploid trophectoderm cells (TE; 233 XY from 16 embryos and 180 XX cells from 12 embryos). Cell numbers from ICM were too sparse to compare. Main results and the role of chance Analysis of XX and XY TE revealed 618 significantly differentially expressed genes (DEGs; 507 upregulated in XX cells, and 111 upregulated in XY cells). These genes are spread across autosomes and sex chromosomes. Interestingly, G6PD is not significantly more highly expressed in XX cells. Gene Ontology (GO) analysis of the XX-biased DEGs revealed a transcriptional sex bias in metabolism-related GO categories, including “mitochondrial ATP synthesis coupled electron transport”, and “respiratory chain complex I”. Gene-level assessment revealed that the drivers of these enrichments are spread across the genome, but 28/64 reside on Chromosome X (hypergeometric p-value = 5.984473e–27), including NDUFA1, NDUFB11, and COX7B (components of the electron transport chain), and SLC25A5 (an ATP/ADP transporter involved in maintaining mitochondrial membrane potential). This indicates a direct role for multiple X-linked genes in sex-biased regulation of embryo metabolism. Metabolic genes that are not sex-biased are distributed across the genome, with no significant enrichment on Chromosome X (76/266, hypergeometric p-value=0.607). Together, these data indicate that GO metabolic term X enrichment is a feature of sex-biased expression and not due to an accumulation of metabolism-related genes on the X. Limitations, reasons for caution This analysis draws on publicly available data, and thus we are unable to perform orthogonal validation of karyotype calls. Additionally, while the initial dataset is large, the quality-filtered dataset (euploid XX and XY TE) is small, and single cell data is infamously variable. Further data collection is required. Wider implications of the findings: Our analysis of sex-biased gene expression in early human embryos suggests a more important role for the X chromosome in modulating sex biases in early embryo metabolism than previously recognized. This study provides insight into the mechanisms underlying the development of metabolic sex differences throughout the lifespan. Trial registration number NA

Abstract 398: Histone Demethylase Kdm6a Contributes To X Chromosome Dependent Ischemia/reperfusion Injury Via Epigenetic Regulation

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Jingyuan Li ◽  
Yuichiro Itoh ◽  
Xuqi Chen ◽  
Arthur Arnold ◽  
Mansoureh Eghbali
Keyword(s):  
Sex Differences ◽  
Carbonic Anhydrase ◽  
X Chromosome ◽  
Epigenetic Regulation ◽  
Ischemia Reperfusion ◽  
Histone Demethylase ◽  
P Value ◽  
Rna Seq ◽  
Female Mice

Introduction: Sex differences in susceptibility to ischemia/reperfusion (I/R) injury have been mostly attributed to sex hormones. Recently we examined the role of sex chromosomes in sex differences in myocardial I/R injury. We discovered that gonadectomized mice with two X chromosomes (XX or XXY) have ~50% larger infarct size after I/R injury, compared to mice with one X chromosome (XY or XO). Only few X genes escape X inactivation and are expressed higher in XX than XY individuals. Here we examined the role of “X escapee” histone demethylase Kdm6a which is important in cardiac development. Methods: Female mice with a heterozygous global knockout of Kdm6a (Kdm6a+/-) and with 2 copies of Kdm6a (Kdm6a+/+, regular WT) were used. Isolated mouse hearts were subjected to 30 min global normothermic ischemia followed by 60 min reperfusion. RNA-Seq analysis was performed by comparing gene expression in hearts of Kdm6a+/+ vs. Kdm6a+/- females at baseline before ischemia. We calculated an unbiased composite score of relevance in which the level of significance of the Kdm6a effect on expression (p value) was integrated with the size of the KDM6A effect on expression (fold change), and with the amount of H3K27me3 mark found on the genes in the heart based on online ChIP-Seq data. Two way ANOVA was used for statistical analysis. P<0.05 was considered statistically significant. Values are expressed as mean± SE. Results: Kdm6a+/+ female mice had significantly lower heart functional recovery compared to their littermate Kdm6a+/- (LVDP: 46.7±9.8% vs. 79.8±3.5%; RPP: 44.1±10.5% vs. 76.2±8.5%, n=6-8 mice/group, p<0.01). The integration of our RNA-Seq data using the hearts of female mice with 2 vs. 1 copy of Kdm6a (n=4 samples per group) with online datasets measuring the H3K27me3 mark, sex differences in expression in humans and mice, and involvement in ischemic heart failure, revealed carbonic anhydrase-3 (Car3) as the most interesting candidate (upregulated ~7 fold in the hearts of Kdm6a+/+ vs. Kdm6a+/- female mice) at baseline. Car3 encodes one isoform of carbonic anhydrase, involved in pH regulation, which is a critical part of I/R injury. Conclusion: Histone demethylase KDM6A contributes to X chromosome dependent I/R injury via epigenetic regulation

scholarly journals Epigenetic mechanisms in sexual differentiation of the brain and behaviour

2016 ◽  
Vol 371 (1688) ◽  
pp. 20150114 ◽  
Author(s):  
Nancy G. Forger
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Sexual Differentiation ◽  
Wide Distribution ◽  
Epigenetic Modifications ◽  
Epigenetic Mechanism ◽  
Epigenetic Mechanisms ◽  
Genome Wide ◽  
The Brain

Circumstantial evidence alone argues that the establishment and maintenance of sex differences in the brain depend on epigenetic modifications of chromatin structure. More direct evidence has recently been obtained from two types of studies: those manipulating a particular epigenetic mechanism, and those examining the genome-wide distribution of specific epigenetic marks. The manipulation of histone acetylation or DNA methylation disrupts the development of several neural sex differences in rodents. Taken together, however, the evidence suggests there is unlikely to be a simple formula for masculine or feminine development of the brain and behaviour; instead, underlying epigenetic mechanisms may vary by brain region or even by dependent variable within a region. Whole-genome studies related to sex differences in the brain have only very recently been reported, but suggest that males and females may use different combinations of epigenetic modifications to control gene expression, even in cases where gene expression does not differ between the sexes. Finally, recent findings are discussed that are likely to direct future studies on the role of epigenetic mechanisms in sexual differentiation of the brain and behaviour.

P–181 Morphine regulates BMP4 growth factor and is involved in in-vitro early embryo development and PGCs formation

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
I Muñoa ◽  
M Araolaza-Lasa ◽  
I Urizar-Arenaza ◽  
M Gianzo Citores ◽  
N Subiran Ciudad
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Environmental Factors ◽  
Embryo Development ◽  
Early Embryo ◽  
Epigenetic Changes ◽  
Morphine Treatment ◽  
Early Embryo Development

Abstract Study question To elucidate if morphine can alter embryo development. Summary answer Chronic morphine treatment regulates BMP4 growth factor, in terms of gene expression and H3K27me3 enrichment and promotes in-vitro blastocysts development and PGC formation. What is known already BMP4 is a member of the bone morphogenetic protein family, which acts mainly through SMAD dependent pathway, to play an important role in early embryo development. Indeed, BMP4 enhances pluripotency in mouse embryonic stem cells (mESCs) and, specifically, is involved in blastocysts formation and primordial germ cells (PGCs) generation. Although, external morphine influence has been previously reported on the early embryo development, focus on implantation and uterus function, there is a big concern in understanding how environmental factors can cause stable epigenetic changes, which could be maintained during development and lead to health problems. Study design, size, duration First, OCT4-reported mESCs were chronically treated with morphine during 24h, 10–5mM. After morphine removal, mESCs were collected for RNA-seq and H3K27me3 ChIP-seq study. To elucidate the role of morphine in early embryo development, two cell- embryos stage were chronically treated with morphine for 24h and in-vitro cultured up to the blastocyst stage in the absence of morphine. Furthermore, after morphine treatment mESCs were differentiated to PGCs, to elucidate the role of morphine in PGC differentiation. Participants/materials, setting, methods Transcriptomic analyses and H3K27me3 genome wide distribution were carried out by RNA-Sequencing and Chip-Sequencing respectively. Validations were performed by RNA-RT-qPCR and Chip-RT-qPCR. Main results and the role of chance Dynamic transcriptional analyses identified a total of 932 differentially expressed genes (DEGs) after morphine treatment on mESCs, providing strong evidence of a transcriptional epigenetic effect induced by morphine. High-throughput screening approaches showed up Bmp4 as one of the main morphine targets on mESCs. Morphine caused an up-regulation of Bmp4 gene expression together with a decrease of H3K27me3 enrichment at promoter level. However, no significant differences were observed on gene expression and H3K27me3 enrichment on BMP4 signaling pathway components (such as Smad1, Smad4, Smad5, Smad7, Prdm1 and Prmd14) after morphine treatment. On the other hand, the Bmp4 gene expression was also up-regulated in in-vitro morphine treated blastocyst and in-vitro morphine treated PGCs. These results were consistent with the increase in blastocyst rate and PGC transformation rate observed after morphine chronic treatment. Limitations, reasons for caution To perform the in-vitro analysis. Further studies are needed to describe the whole signaling pathways underlying BMP4 epigenetic regulation after morphine treatment. Wider implications of the findings: Our findings confirmed that mESCs and two-cell embryos are able to memorize morphine exposure and promote both blastocyst development and PGCs formation through potentially BMP4 epigenetic regulation. These results provide insights understanding how environmental factors can cause epigenetic changes during the embryo development, leading to alterations and producing health problems/diseases Trial registration number Not applicable

scholarly journals Distinct molecular etiologies of male and female hepatocellular carcinoma

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Heini M. Natri ◽  
Melissa A. Wilson ◽  
Kenneth H. Buetow
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Sex Differences ◽  
Differential Expression ◽  
Differential Expression Analysis ◽  
Regulation Of Transcription ◽  
Male And Female ◽  
Differential Effects ◽  
Pathway Enrichment

Abstract Background Sex-differences in cancer occurrence and mortality are evident across tumor types; men exhibit higher rates of incidence and often poorer responses to treatment. Targeted approaches to the treatment of tumors that account for these sex-differences require the characterization and understanding of the fundamental biological mechanisms that differentiate them. Hepatocellular Carcinoma (HCC) is the second leading cause of cancer death worldwide, with the incidence rapidly rising. HCC exhibits a male-bias in occurrence and mortality, but previous studies have failed to explore the sex-specific dysregulation of gene expression in HCC. Methods Here, we characterize the sex-shared and sex-specific regulatory changes in HCC tumors in the TCGA LIHC cohort using combined and sex-stratified differential expression and eQTL analyses. Results By using a sex-specific differential expression analysis of tumor and tumor-adjacent samples, we uncovered etiologically relevant genes and pathways differentiating male and female HCC. While both sexes exhibited activation of pathways related to apoptosis and cell cycle, males and females differed in the activation of several signaling pathways, with females showing PPAR pathway enrichment while males showed PI3K, PI3K/AKT, FGFR, EGFR, NGF, GF1R, Rap1, DAP12, and IL-2 signaling pathway enrichment. Using eQTL analyses, we discovered germline variants with differential effects on tumor gene expression between the sexes. 24.3% of the discovered eQTLs exhibit differential effects between the sexes, illustrating the substantial role of sex in modifying the effects of eQTLs in HCC. The genes that showed sex-specific dysregulation in tumors and those that harbored a sex-specific eQTL converge in clinically relevant pathways, suggesting that the molecular etiologies of male and female HCC are partially driven by differential genetic effects on gene expression. Conclusions Sex-stratified analyses detect sex-specific molecular etiologies of HCC. Overall, our results provide new insight into the role of inherited genetic regulation of transcription in modulating sex-differences in HCC etiology and provide a framework for future studies on sex-biased cancers.

scholarly journals Distinct molecular etiologies of male and female hepatocellular carcinoma

2019 ◽  
Author(s):  
Heini M Natri ◽  
Melissa A Wilson ◽  
Kenneth H Buetow
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Sex Differences ◽  
Differential Expression ◽  
Differential Expression Analysis ◽  
Regulation Of Transcription ◽  
Male And Female ◽  
Differential Effects ◽  
Pathway Enrichment

Abstract Background: Sex-differences in cancer occurrence and mortality are evident across tumor types; men exhibit higher rates of incidence and often poorer responses to treatment. Targeted approaches to the treatment of tumors that account for these sex-differences require the characterization and understanding of the fundamental biological mechanisms that differentiate them. Hepatocellular Carcinoma (HCC) is the second leading cause of cancer death worldwide, with the incidence rapidly rising. HCC exhibits a male-bias in occurrence and mortality, but previous studies have failed to explore the sex-specific dysregulation of gene expression in HCC. Methods: Here, we characterize the sex-shared and sex-specific regulatory changes in HCC tumors in the TCGA LIHC cohort using combined and sex-stratified differential expression and eQTL analyses. Results: By using a sex-specific differential expression analysis of tumor and tumor-adjacent samples, we uncovered etiologically relevant genes and pathways differentiating male and female HCC. While both sexes exhibited activation of pathways related to apoptosis and cell cycle, males and females differed in the activation of several signaling pathways, with females showing PPAR pathway enrichment while males showed PI3K, 305 PI3K/AKT, FGFR, EGFR, NGF, GF1R, Rap1, DAP12, and IL-2 signaling pathway enrichment. Using eQTL analyses, we discovered germline variants with differential effects on tumor gene expression between the sexes. 24.3% of the discovered eQTLs exhibit differential effects between the sexes, illustrating the substantial role of sex in modifying the effects of eQTLs in HCC. The genes that showed sex-specific dysregulation in tumors and those that harbored a sex-specific eQTL converge in clinically relevant pathways, suggesting that the molecular etiologies of male and female HCC are partially driven by differential genetic effects on gene expression. Conclusions: Sex-stratified analyses detect sex-specific molecular etiologies of HCC. Overall, our results provide new insight into the role of inherited genetic regulation of transcription in modulating sex-differences in HCC etiology and provide a framework for future studies on sex-biased cancers.

scholarly journals Distinct molecular etiologies of male and female hepatocellular carcinoma

2019 ◽  
Author(s):  
Heini M Natri ◽  
Melissa A Wilson ◽  
Kenneth H Buetow
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Sex Differences ◽  
Differential Expression ◽  
Differential Expression Analysis ◽  
Regulation Of Transcription ◽  
Male And Female ◽  
Differential Effects ◽  
Pathway Enrichment

Abstract Background: Sex-differences in cancer occurrence and mortality are evident across tumor types; men exhibit higher rates of incidence and often poorer responses to treatment. Targeted approaches to the treatment of tumors that account for these sex-differences require the characterization and understanding of the fundamental biological mechanisms that differentiate them. Hepatocellular Carcinoma (HCC) is the second leading cause of cancer death worldwide, with the incidence rapidly rising. HCC exhibits a male-bias in occurrence and mortality, but previous studies have failed to explore the sex-specific dysregulation of gene expression in HCC. Methods: Here, we characterize the sex-shared and sex-specific regulatory changes in HCC tumors in the TCGA LIHC cohort using combined and sex-stratified differential expression and eQTL analyses. Results: By using a sex-specific differential expression analysis of tumor and tumor-adjacent samples, we uncovered etiologically relevant genes and pathways differentiating male and female HCC. While both sexes exhibited activation of pathways related to apoptosis and cell cycle, males and females differed in the activation of several signaling pathways, with females showing PPAR pathway enrichment while males showed PI3K, 305 PI3K/AKT, FGFR, EGFR, NGF, GF1R, Rap1, DAP12, and IL-2 signaling pathway enrichment. Using eQTL analyses, we discovered germline variants with differential effects on tumor gene expression between the sexes. 24.3% of the discovered eQTLs exhibit differential effects between the sexes, illustrating the substantial role of sex in modifying the effects of eQTLs in HCC. The genes that showed sex-specific dysregulation in tumors and those that harbored a sex-specific eQTL converge in clinically relevant pathways, suggesting that the molecular etiologies of male and female HCC are partially driven by differential genetic effects on gene expression. Conclusions: Sex-stratified analyses detect sex-specific molecular etiologies of HCC. Overall, our results provide new insight into the role of inherited genetic regulation of transcription in modulating sex-differences in HCC etiology and provide a framework for future studies on sex-biased cancers.

scholarly journals Hybrid assembly of the genome of the entomopathogenic nematode Steinernema carpocapsae identifies the X-chromosome

2019 ◽  
Author(s):  
Lorrayne Serra ◽  
Marissa Macchietto ◽  
Aide Macias-Muñoz ◽  
Cassandra Joan McGill ◽  
Isaryhia Maya Rodriguez ◽  
...  
Keyword(s):  
Gene Expression ◽  
X Chromosome ◽  
Genetic Model ◽  
Biological Control Agent ◽  
Gc Content ◽  
Steinernema Carpocapsae ◽  
Comparative Genomic ◽  
Chromosome X ◽  
C Elegans ◽  
Long Reads

AbstractEntomopathogenic nematodes from the genus Steinernema are lethal insect parasites that quickly kill their insect hosts with the help of their symbiotic bacteria. Steinernema carpocapsae is one of the most studied entomopathogens due to its broad lethality to diverse insect species and its effective commercial use as a biological control agent for insect pests, as well as a genetic model for studying parasitism, pathogenesis, and symbiosis. In this study, we used long-reads from the Pacific Biosciences platform and BioNano Genomics Irys system to assemble the best genome of S. carpocapsae ALL strain to date, comprising 84.5 Mb in 16 scaffolds, with an N50 of 7.36Mb. The largest scaffold, with 20.9Mb, was identified as chromosome X based on sex-specific genome sequencing. The high level of contiguity allowed us to characterize gene density, repeat content, and GC content. RNA-seq data from 17 developmental stages, spanning from embryo to adult, were used to predict 30,957 gene models. Using this new genome, we performed a macrosyntenic analysis to Caenorhabditis elegans and Pristionchus pacificus and found S. carpocapsae’s chromosome X to be primarily orthologous to C. elegans’ and P. pacificus’ chromosome II and IV. We also investigated the expansion of protein families and gene expression differences between male and female stage nematodes. This new genome and more accurate set of annotations provide a foundation for new comparative genomic and gene expression studies within the Steinernema clade and across the Nematoda phylum.Article SummaryThe insect killing worms Steinernema carpocapsae is a model organism for parasitism and symbiosis. The authors have used long reads and optical mapping to generate substantially contiguous assembly and a new set of gene annotations. They have identified the X chromosome as well as expansions in specific family proteases found in the venom of this worm. A macrosyntenic analysis with C. elegans shows a broad conservation of ancestral chromosomes with the exception of chromosome X. This new assembly will be useful to the Steinernema community and the broader nematode genomics community.

scholarly journals A role of polycomb group genes in the regulation of gap gene expression in Drosophila.

Genetics ◽  
1994 ◽  
Vol 136 (4) ◽  
pp. 1341-1353 ◽  
Author(s):  
F Pelegri ◽  
R Lehmann
Keyword(s):  
Gene Expression ◽  
Small Region ◽  
Early Embryo ◽  
Polycomb Group ◽  
Drosophila Embryo ◽  
Polycomb Group Genes ◽  
Gap Gene ◽  
Anteroposterior Polarity

Abstract Anteroposterior polarity of the Drosophila embryo is initiated by the localized activities of the maternal genes, bicoid and nanos, which establish a gradient of the hunchback (hb) morphogen. nanos determines the distribution of the maternal Hb protein by regulating its translation. To identify further components of this pathway we isolated suppressors of nanos. In the absence of nanos high levels of Hb protein repress the abdomen-specific genes knirps and giant. In suppressor-of-nanos mutants, knirps and giant are expressed in spite of high Hb levels. The suppressors are alleles of Enhancer of zeste (E(z)) a member of the Polycomb group (Pc-G) of genes. We show that E(z), and likely other Pc-G genes, are required for maintaining the expression domains of knirps and giant initiated by the maternal Hb protein gradient. We have identified a small region of the knirps promoter that mediates the regulation by E(z) and hb. Because Pc-G genes are thought to control gene expression by regulating chromatin, we propose that imprinting at the chromatin level underlies the determination of anteroposterior polarity in the early embryo.

Gene Expression Profile of Protein Kinases Reveals a Distinctive Signature of Chronic Lymphocytic Leukemia (CLL) and Points to a Role of Second Generation Protein Kinase Inhibitors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2794-2794
Author(s):  
Simona Tavolaro ◽  
Sabina Chiaretti ◽  
Monica Messina ◽  
Francesca R. Mauro ◽  
Ilaria Del Giudice ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prognostic Factors ◽  
Protein Kinase ◽  
Chronic Lymphocytic Leukemia ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Kinase Activity ◽  
Lymphocytic Leukemia ◽  
P Value

Abstract Background. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of relatively mature B cells and by a very variable clinical course. This clinical heterogeneity is sustained by different biologic parameters, such as the mutational status of the immunoglobulin variable genes (IgVH), CD38 and ZAP-70 expression. In order to investigate the potential role of protein kinase (PK) inhibitors in CLL, we evaluated the gene expression profile of 1324 probesets annotated as PK using the HGU133 Plus2.0 Affymetrix arrays. Methods. We evaluated 44 CLL and 137 acute lymphocytic leukemia (ALL) patients. Two additional sets of CLL (49 cases) were utilized to validate the results obtained. Probesets identified as PK genes were used for all the analyses, namely unsupervised clustering, Analysis of Variance (ANOVA) and t-test analysis. ANOVA was performed using a p-value of ≤0.001: further selection was performed retaining only those probesets whose mean expression level was ≥300 in at least one group and showed a fold change difference of ≥1.5 across all groups. Finally, to specifically identify genes differentially expressed between different subclasses of CLL, a t-test was applied: probesets were required to have a p-value ≤0.05 and a fold change>1.5. Results. Unsupervised analysis, performed on CLL samples and different ALL subgroups, highlighted in CLL a unique and very homogeneous pattern characterized by the overexpression of a large set of PK; these results were further confirmed by ANOVA. Moreover, we identified 16 PK genes that were highly expressed in all 3 CLL sets analyzed. These genes codify for proteins with tyrosine kinase activity (SYK, LYN, BLK, LCK, JAK1, CSK and FGR), serin-threonin kinase activity (PIM2, PFTK1, TLK1, MAP4K1, PDPK1, PRKCB1 and STK10) or both (GRK6 and WEE1). Some of the selected genes are members of important protein kinase families, involved in cellular signaling, such as Src kinases (SFK), MAPK and JAK kinase family. PK expression was also analyzed in different CLL subclasses, subdivided according to different prognostic factors; in particular, we compared IgVH mutated vs unmutated patients, CD38+ vs CD38- cases and, finally, ZAP-70+ vs ZAP-70- patients in the 3 experimental CLL sets. Comparison between IgVH mutated vs unmutated cases highlighted a differential expression of ZAP-70 in all the 3 sets analyzed. Contrariwise, no PK was associated with the other prognostic parameters. Thus, these analyses did not show a specific signature associated with the abovementioned biologic features, suggesting that PK overexpression is specific of the disease itself rather than of CLL subclasses. Conclusions. Our results show that CLL is characterized by a very peculiar PK signature and identify some potential molecular targets. Moreover, our findings indicate that a common mechanism of PK-mediated deregulation is operational in CLL cells, independently of other prognostic factors. Based on these pre-clinical data, we propose that second generation PK inhibitors may have a role in the management of all CLL patients.

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