Anagh A Sahasrabuddhe

• PhD
• Research Associate at University of Pennsylvania

The polycomb group protein BMI1 has been linked to proliferation, senescence, cancer progression and stem cell phenotype. At present, very little is known about its regulation. Here, we report that BMI1 contains a functional recognition motif for the F box protein βTrCP, which regulates ubiquitination and proteasome-mediated degradation of various...

EZH2 (enhancer of zeste homolog 2) is a critical enzymatic subunit of the polycomb repressive complex 2 (PRC2), which trimethylates histone H3 (H3K27) to mediate gene repression. Somatic mutations, overexpression and hyperactivation of EZH2 have been implicated in the pathogenesis of several forms of cancer. In particular, recurrent gain-of-functio...

Se´zary syndrome (SS) is an aggressive leukaemia of mature T cells with poor prognosis and limited options for targeted therapies. The comprehensive genetic alterations underlying the pathogenesis of SS are unknown. Here we integrate whole-genome sequencing (n¼6), whole-exome sequencing (n¼66) and array comparative genomic hybridization-based copyn...

Ubiquitination is a post-translational modification process that regulates several critical cellular processes. Ubiquitination is orchestrated by the ubiquitin proteasome system (UPS), which constitutes a cascade of enzymes that transfer ubiquitin onto protein substrates. The UPS catalyzes the destruction of many critical protein substrates involve...

The role of ubiquitin-mediated degradation mechanisms in the pathogenesis of diffuse large B-cell lymphoma (BCL) and follicular lymphoma is not completely understood. We show that conditional deletion of the E3 ubiquitin ligase Fbxo45 in germinal center B cells results in B-cell lymphomagenesis in homozygous (100%) and heterozygous (48%) mice. Mech...

A fundamental requirement for growth of rapidly proliferating cells is metabolic adaptation to promote synthesis of biomass. ATP citrate lyase (ACLY) is a critical enzyme responsible for synthesis of cytosolic acetyl-CoA, the key building component for de novo fatty acid synthesis and links vital pathways such as carbohydrate and lipid metabolism....

Mechanisms by which NPM-ALK signaling regulates cell migration, invasion and contributes to the oncogenesis of anaplastic large cell lymphoma (ALCL) are not completely understood. In an attempt to identify novel actin signaling pathways regulated by NPM-ALK, a comprehensive phosphoproteome analysis of ALCL cell lines was performed in the presence o...

BMI1 oncogene is a catalytic member of epigenetic repressor polycomb group proteins. It plays a critical role in the regulation of gene expression pattern and consequently several cellular processes during development, including cell cycle progression, senescence, aging, apoptosis, angiogenesis, and importantly self-renewal of adult stem cells of s...

Background: EZH2 is a critical enzymatic subunit of the PRC2 which trimethylates histone H3 (H3K27me3) to mediate gene repression. The recurrent gain-of-function somatic mutations in EZH2, at Y641 residue have been recently reported in germinal center B-cell (GCB) derived lymphomas. Consequently, B-cell lymphoma cell lines and lymphoma primary samp...

Supplementary Figure 1. Experimental paradigm. A combination of genome and exome sequencing coupled with array-comparative genome hybridization was performed on a total of 85 SS patients. Data filtration identified 463 genes with recurrent loss of function lesions. Of these, we focused our attention on 16 genes which included 75 mutations. For 35 o...

Deregulated proteolysis is increasingly being implicated in pathogenesis of lymphoma. In this review, we highlight the major cellular processes that are affected by deregulated proteolysis of critical substrates that promote lymphoproliferative disorders. Emerging evidence supports the role of aberrant proteolysis by the ubiquitin proteasome system...

Provided herein are kits, compositions and methods for cancer diagnosis, research and therapy, including but not limited to, cancer markers. In particular, the present invention relates to recurrent RNA fusions as diagnostic markers and clinical targets for leukemia.

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Introduction: Enhancer of zeste homologue 2 (EZH2) is a critical enzymatic subunit of the polycomb repressive complex 2 (PRC2) which trimethylates histone H3 (H3K27) to mediate gene repression. EZH2 is aberrantly activated and overexpressed in several hematologic malignancies and is associated with aggressive clinical behavior. In particular, recur...

Introduction: Enhancer of zeste homologue 2 (EZH2) is a critical enzymatic subunit of the polycomb repressive complex 2 (PRC2) which trimethylates histone H3 (H3K27) to mediate gene repression. EZH2 is aberrantly activated and overexpressed in several hematologic malignancies and is associated with aggressive clinical behavior. In particular, recur...

Introduction Sezary Syndrome (SS) is an aggressive mature T-cell neoplasm characterized by erythroderma, generalized lymphadenopathy and circulating T-cells. SS cells are characterized by complex karyotypes with numerous structural alterations and copy-number variants. Previous studies have implicated disruption and/or haploinsufficiency of TP53, C...

Introduction: The CD30-positive cutaneous T-cell lymphoproliferative disorders (CD30-positive LPD) include lymphomatoid papulosis (LYP) and primary cutaneous anaplastic large cell lymphoma (ALCL). Recurrent chromosomal translocations frequently underlie the pathogenesis of several hematologic malignancies and often define molecular subtypes with di...

The spectrum of cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Chromosomal translocations targeting tyrosine kinases in CD30-positive LPDs have not been described. Using whole-transcriptome sequencing, we identified a chimeric fusion involving NPM1 (...

Fbxo45 is an atypical E3 ubiquitin ligase, which specifically targets proteins for ubiquitin-mediated degradation. Fbxo45 ablation results in defective neuronal differentiation and abnormal formation of neural connections; however, the mechanisms underlying these defects are poorly understood. Using an unbiased mass spectrometry-based proteomic scr...

The present invention relates to methods and biomarkers for detection and characterization of mature T-cell neoplasias/leukemias (e.g., T-cell prolymphocytic leukemia, Sezary syndrome) in biological samples (e.g., tissue samples, blood samples, plasma samples, cell samples, serum samples).

Prostate apoptosis response protein 4 (Par-4) also known as PRKC apoptosis WT1 regulator is a tumor suppressor that selectively induces apoptosis in cancer cells. However, its post-translational regulation by ubiquitin-mediated proteolysis and the cellular machinery that is responsible for its proteasomal degradation are unknown. Using immunopurifi...

The comprehensive genetic alterations underlying the pathogenesis of T-cell prolymphocytic leukemia (T-PLL) are unknown. To address this, we performed whole-genome sequencing (WGS), whole-exome sequencing (WES), high-resolution copy-number analysis, and Sanger resequencing of a large cohort of T-PLL. WGS and WES identified novel mutations in recurr...

EZH2 is a critical enzymatic subunit of the PRC2 which trimethylates histone H3 (H3K27) to mediate gene repression. While overexpression of EZH2 and its increased H3K27 methylation have generally been associated with hematologic malignancies and solid tumors, recurrent gain of function somatic mutations in EZH2 have been recently reported in germin...

EZH2 is a critical enzymatic subunit of the PRC2 which trimethylates histone H3 (H3K27) to mediate gene repression. While overexpression of EZH2 and its increased H3K27 methylation have generally been associated with hematologic malignancies and solid tumors, recurrent gain of function somatic mutations in EZH2 have been recently reported in germin...

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in the Western hemisphere. Tumor-specific chromosomal translocations, characteristic findings in several human malignancies that directly lead to malignant transformation, have not been identified in CLL. Using paired-end transcriptome sequencing, we identified recurre...

Introduction: Anaplastic large cell lymphoma (ALCL) is a subtype of mature T cell lymphoma. The NPM-ALK fusion protein is expressed in 80% of pediatric ALCL and arises from a chromosomal translocation t(2;5)(p23;q35). NPM-ALK is a constitutively active oncogenic tyrosine kinase that regulates the function of numerous proteins involved in apoptosis...

Introduction: Anaplastic large cell lymphoma (ALCL) is a subtype of mature T cell lymphoma. The NPM­ALK fusion protein is expressed in 80% of pediatric ALCL and arises from a chromosomal translocation t(2;5)(p23;q35). NPM­ALK is a constitutively active oncogenic tyrosine kinase that regulates the function of numerous proteins involved in apoptosis...

1535 Introduction Anaplastic large cell lymphoma (ALCL) is a subtype of mature T cell lymphoma. The NPM-ALK fusion protein is expressed in 80% of pediatric ALCL and arises from a chromosomal translocation t(2;5)(p23;q35). NPM-ALK is a constitutively active oncogenic tyrosine kinase that regulates the function of numerous proteins involved in apopt...

Polycomb group (PcG) proteins are overexpressed in several human malignancies including breast cancer. In particular, aberrant expression of BMI1 and EZH2 has been linked to metastasis and poor prognosis in cancer patients. At present, very little is known about the pharmacological inhibitors of PcG proteins. Here we show that histone deacetylase i...

Supplementary data. The additional file contains Figure legends and Figures S1-S6.

The polycomb group (PcG) protein BMI1 is an important regulator of development. Additionally, aberrant expression of BMI1 has been linked to cancer stem cell phenotype and oncogenesis. In particular, its overexpression has been found in several human malignancies including breast cancer. Despite its established role in stem cell maintenance, cancer...

The polycomb group (PcG) protein, enhancer of zeste homologue 2 (EZH2), is overexpressed in several human malignancies including breast cancer. Aberrant expression of EZH2 has been associated with metastasis and poor prognosis in cancer patients. Despite the clear role of EZH2 in oncogenesis and therapy failure, not much is known about chemotherape...

We have examined the A431 (human epidermoid carcinoma) and HT29 (human colorectal carcinoma) cellular responses evoked by lectins of dietary origin, Jacalin of Artocarpus integrifolia (native jacalin; nJacalin), peanut agglutinin (PNA) of Arachis hypogea, and recombinant single-chain jacalin (rJacalin), which has the same protein backbone but ;100-...

Sugar binding studies, inactivation, unfolding, and refolding of native Jacalin (nJacalin) from Artocarpus integrifolia and recombinant single-chain Jacalin (rJacalin) expressed in Escherichia coli were studied by intrinsic fluorescence and thermal and chemical denaturation approaches. Interestingly, rJacalin does not undergo any proteolytic proces...

Assembly and penetration of 14-strand beta-barrel of staphylococcal alpha-hemolysin (alpha-HL) is an intriguing phenomenon due to its water soluble property. alpha-HL interacts with the Caveolin-1 of A431 cells for its rapid assembly. A nine amino acid, non-hydrophobic peptide derived from alpha-HL has been shown to block the interaction of alpha-H...