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1.
Am J Hematol ; 96(6): 698-707, 2021 06 01.
Article in English | MEDLINE | ID: mdl-33761144

ABSTRACT

Myeloproliferative neoplasms (MPNs) are characterized by a pathologic expansion of myeloid lineages. Mutations in JAK2, CALR and MPL genes are known to be three prominent MPN disease drivers. Mutant CALR (mutCALR) is an oncoprotein that interacts with and activates the thrombopoietin receptor (MPL) and represents an attractive target for targeted therapy of CALR mutated MPN. We generated a transgenic murine model with conditional expression of the human mutant exon 9 (del52) from the murine endogenous Calr locus. These mice develop essential thrombocythemia like phenotype with marked thrombocytosis and megakaryocytosis. The disease exacerbates with age showing prominent signs of splenomegaly and anemia. The disease is transplantable and mutCALR stem cells show proliferative advantage when compared to wild type stem cells. Transcriptome profiling of hematopoietic stem cells revealed oncogenic and inflammatory gene expression signatures. To demonstrate the applicability of the transgenic animals for immunotherapy, we treated mice with monoclonal antibody raised against the human mutCALR. The antibody treatment lowered platelet and stem cell counts in mutant mice. Secretion of mutCALR did not constitute a significant antibody sink. This animal model not only recapitulates human MPN but also serves as a relevant model for testing immunotherapeutic strategies targeting epitopes of the human mutCALR.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Calreticulin/antagonists & inhibitors , Disease Models, Animal , Hematopoietic Stem Cells/metabolism , Molecular Targeted Therapy , Thrombocythemia, Essential/therapy , Animals , Antibodies, Monoclonal/immunology , Blood Platelets/immunology , Blood Platelets/metabolism , Calreticulin/genetics , Calreticulin/immunology , Calreticulin/physiology , Exons/genetics , Frameshift Mutation , Gene Knock-In Techniques , Immunotherapy , Mice , Mice, Inbred C57BL , Mice, Transgenic , Radiation Chimera , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Sequence Deletion , Splenomegaly/etiology , Thrombocythemia, Essential/blood , Thrombocythemia, Essential/complications , Thrombocythemia, Essential/genetics , Transcriptome
2.
Crit Rev Oncol Hematol ; 151: 102964, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32464482

ABSTRACT

Breast Cancer is the most predominant female cancer in developed as well as developing countries. The treatment strategies of breast cancers depends on an array of factors like age at diagnosis, menstrual status, dietary pattern, immunological response, genetic variations of the cancer cells etc. Recent technological advancements in cancer diagnosis lead to the emergence of gene expression pattern for better understanding of the tumor behavior. It has not only bolstered the prognosis, but also the early diagnosis and therapy. The accuracy in disease prognosis can be boosted when gene expression signatures are combined with traditional clinicopathological features. This review explains how the evolution of gene expression signatures for breast cancers, its advantages and future prospects. In addition, an overview of currently available gene expression signature analysis tools and consolidated information on their current status and specific benefits, that can be availed for breast cancer diagnosis are also discussed.


Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/therapy , Breast Neoplasms/pathology , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Prognosis , Transcriptome
3.
Carcinogenesis ; 41(5): 611-624, 2020 07 10.
Article in English | MEDLINE | ID: mdl-31219560

ABSTRACT

Gestational trophoblastic diseases (GTD) are group of pregnancy-related tumors characterized by abnormal levels of 'ß-hCG' with higher incidence in South-East Asia, especially India. Our laboratory has reported that wild-type BRCA1 transcriptionally regulates ß-hCG in triple negative breast cancers (TNBCs). These factors culminated into analysis of BRCA1 status in GTD, which would emanate into elucidation of BRCA1- ß-hCG relationship and unraveling etio-pathology of GTD. BRCA1 level in GTD is down-regulated due to the over-expression of DNMT3b and subsequent promoter hypermethylation, when compared to the normal placentae accompanied with its shift in localization. There is an inverse correlation of serum ß-hCG levels with BRCA1 mRNA expression. The effects of methotrexate (MTX), which is the first-line chemotherapeutic used for GTD treatment, when analyzed in comparison with plumbagin (PB) revealed that PB alone is efficient than MTX alone or MTX-PB in combination, in showing selective cytotoxicity against GTD. Interestingly, PB increases BRCA1 levels post-treatment, altering DNMT3b levels and resultant BRCA1 promoter methylation. Also, cohort study analyzed the incidence of GTD at Sree Avittom Thirunal (SAT) Hospital, Thiruvananthapuram, which points out that 11.5% of gestational trophoblastic neoplasia (GTN) cases were referred to Regional Cancer Centre, Thiruvananthapuram, for examination of breast lumps. This has lend clues to supervene the risk of GTD patients towards BRCA1-associated diseases and unveil novel therapeutic for GTD, a plant-derived naphthoquinone, PB, already reported as selectively cytotoxic against BRCA1 defective tumors.


Subject(s)
BRCA1 Protein/genetics , Chorionic Gonadotropin, beta Subunit, Human/metabolism , DNA Methylation , Gestational Trophoblastic Disease/pathology , Mutation , Placenta/metabolism , Promoter Regions, Genetic , Adult , Antineoplastic Agents/pharmacology , Apoptosis , BRCA2 Protein/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Proliferation , Chorionic Gonadotropin, beta Subunit, Human/genetics , Cohort Studies , Female , Gene Expression Regulation, Neoplastic , Gestational Trophoblastic Disease/drug therapy , Gestational Trophoblastic Disease/genetics , Gestational Trophoblastic Disease/metabolism , Humans , Placenta/drug effects , Placenta/pathology , Pregnancy , Pregnancy Complications/drug therapy , Pregnancy Complications/genetics , Pregnancy Complications/metabolism , Pregnancy Complications/pathology , Prognosis , Trophoblastic Neoplasms/drug therapy , Trophoblastic Neoplasms/genetics , Trophoblastic Neoplasms/metabolism , Trophoblastic Neoplasms/pathology , Tumor Cells, Cultured
4.
Semin Oncol ; 44(4): 254-264, 2017 08.
Article in English | MEDLINE | ID: mdl-29526253

ABSTRACT

Chromosome 17 (Chr17) harbors crucial genes that encode proteins implicated in a variety of cancers, including some that guard cancer cells from genomic instability and others that interfere with metastasis. Included amongst the genes on chr17 that regulate biological processes fundamental to the genesis of cancer are TP53, BRCA1, CCL5, NF-1, and GRB7. As many as 50% of all human tumors and at least 30% of breast carcinomas contain p53 mutations, while 30%-40% of breast cancers have defective BRCA1. A large number of proteins regulate the expression of these cancer genes on chr17 with miRNAs, the most widely studied class of regulatory RNAs, playing a major role in epigenetically controlling the gene expression programs, thereby managing various cellular functions. This review provides information on the genes transcribed from chr17, and their regulation by miRNAs in the context to tumorigenesis located on chr17, along with an analysis of the receptor status (estrogen, progesterone, and Her2/Neu) from the miRNA prediction data of miRNA genes located on chr17.


Subject(s)
Chromosomes, Human, Pair 17 , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Gene Regulatory Networks , Humans
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