Papers by Anil Sadarangani
Tumor necrosis factor (TNF)-α promotes tumor development under chronic inflammation. Because TNF ... more Tumor necrosis factor (TNF)-α promotes tumor development under chronic inflammation. Because TNF also activates caspase-8, selective inhibition of TNF-induced extrinsic apoptosis would be required for inflammation-associated tumor growth. In a mouse model of inflammation-associated colon carcinogenesis, we found nuclear expression of β-catenin in tumors of wild-type, but not mutant, mice that were made resistant to TNF-induced apoptosis by a germline mutation blocking caspase cleavage of the retinoblastoma (RB) protein, despite similar frequencies of β-catenin exon-3 mutations in these two genetic backgrounds. TNF-induced apoptosis was also attenuated in human colon cancer cell lines with genetically activated β-catenin. However, we found that HCT116 cells, which contain an activated allele of β-catenin but do not express nuclear β-catenin, were sensitive to TNF-induced apoptosis. In HCT116 cells, TNF stimulated efficient RB cleavage that preceded chromatin condensation. In contrast...
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Cell Stem Cell, 2013
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Blood, 2012
2772 While advanced malignancies in Chronic Myeoloid Leukemia (CML) are diverse in phenotype, the... more 2772 While advanced malignancies in Chronic Myeoloid Leukemia (CML) are diverse in phenotype, they often exhibit stem cell properties including enhanced survival, quiescence and self-renewal potential. The molecular etiology of human progenitor reprogramming into self-renewing leukemia stem cells (LSC) has remained elusive. While DNA sequencing has uncovered spliceosome gene mutations that promote alternative splicing and portend leukemic transformation, isoform diversity may also be generated by aberrant RNA editing mediated by adenosine deaminase acting on dsRNA (ADAR) family, which have been shown to promote an embryonic transcriptional program and regulate fetal and adult hematopoietic stem cell (HSC) self-renewal as well as stem cell responses to inflammation. In this study, whole transcriptome sequencing of normal, chronic phase (CP) and functionally validated blast crisis (BC) chronic myeloid leukemia (CML) progenitors revealed increased inflammatory pathway gene expression i...
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Reproductive Sciences, 2014
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Molecular Cancer Research, 2013
Tumor necrosis factor (TNF)-α promotes tumor development under chronic inflammation. Because TNF ... more Tumor necrosis factor (TNF)-α promotes tumor development under chronic inflammation. Because TNF also activates caspase-8, selective inhibition of TNF-induced extrinsic apoptosis would be required for inflammation-associated tumor growth. In a mouse model of inflammation-associated colon carcinogenesis, we found nuclear expression of β-catenin in tumors of wild-type, but not mutant, mice that were made resistant to TNF-induced apoptosis by a germline mutation blocking caspase cleavage of the retinoblastoma (RB) protein, despite similar frequencies of β-catenin exon-3 mutations in these two genetic backgrounds. TNF-induced apoptosis was also attenuated in human colon cancer cell lines with genetically activated β-catenin. However, we found that HCT116 cells, which contain an activated allele of β-catenin but do not express nuclear β-catenin, were sensitive to TNF-induced apoptosis. In HCT116 cells, TNF stimulated efficient RB cleavage that preceded chromatin condensation. In contrast...
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Proceedings of the National Academy of Sciences, 2012
The molecular etiology of human progenitor reprogramming into self-renewing leukemia stem cells (... more The molecular etiology of human progenitor reprogramming into self-renewing leukemia stem cells (LSC) has remained elusive. Although DNA sequencing has uncovered spliceosome gene mutations that promote alternative splicing and portend leukemic transformation, isoform diversity also may be generated by RNA editing mediated by adenosine deaminase acting on RNA (ADAR) enzymes that regulate stem cell maintenance. In this study, whole-transcriptome sequencing of normal, chronic phase, and serially transplantable blast crisis chronic myeloid leukemia (CML) progenitors revealed increased IFN-γ pathway gene expression in concert with BCR-ABL amplification, enhanced expression of the IFN-responsive ADAR1 p150 isoform, and a propensity for increased adenosine-to-inosine RNA editing during CML progression. Lentiviral overexpression experiments demonstrate that ADAR1 p150 promotes expression of the myeloid transcription factor PU.1 and induces malignant reprogramming of myeloid progenitors. Mor...
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AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 4366 Ovarian cancer constitutes one of the m... more AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 4366 Ovarian cancer constitutes one of the main causes of death from gynecological cancers worldwide. In spite of an excellent initial response with the use of aggressive cytoreductive surgery plus adjuvant chemotherapy the overall survival is poor. Thus, finding of new modalities of treatments remains a major challenge when dealing with advanced stages of this disease. During last years evidence has been published supporting pleitropic effects of statins beyond their better known effect, this is, the cardioprotective effect due to beneficial changes in lipid metabolism and in the inflammatory response involved in atheroma plaque formation. Statins, HMG-CoA reductase inhibitors, would induce cell death in some epithelial cancers (i.e. breast cancer) but the explanatory mechanisms are not well characterized. Objectives: We investigated if statins induce apoptosis in ovarian cancer cell lines and what are the mechanisms explaining t...
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Blood
1693 The aim of this study is to develop clinical strategies that will HALT progression of CML by... more 1693 The aim of this study is to develop clinical strategies that will HALT progression of CML by reducing leukemia stem cell (LSC) burden using a clinical grade JAK2 inhibitor, SAR302503 (SAR503, Sanofi, Cambridge, MA), alone or in combination with a potent BCR-ABL inhibitor, dasatinib. For this, CML patient samples in blast crisis phase (BC CML) were subjected to immunomagnetic bead CD34 selection or FACS Aria ll sorted to obtain leukemic progenitors (LSC/CD34+CD38+Lin−). Malignant progenitors were then transplanted into neonatal RAG2−/−gc−/− mice, and 8 weeks post-transplant, mice were treated with SAR503, dasatinib and vehicle for 14 days. Following treatment, hematopoietic tissues were analyzed for human engraftment by FACS analysis. Our results revealed that single agent experiments with SAR503 had a cytostatic rather than a cytoreductive effect on BC LSC. The treatment alone (60 mg/kg twice daily administered by oral gavage) did not significantly reduce leukemic progenitor bu...
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Blood
Introduction Leukemia stem cells (LSC) in chronic myeloid leukemia (CML) are important in disease... more Introduction Leukemia stem cells (LSC) in chronic myeloid leukemia (CML) are important in disease progression and relapse. Conventional therapy with tyrosine kinase inhibitors (TKIs), although very effective at reducing bulk CML cells, frequently fail to eliminate LSC residing in the protective bone marrow niche. Thus, there is an unmet need for combination therapy that simultaneously targets bulk disease and eliminates LSC in order to prevent disease progression and relapse. Stem cell niches are often rich in hyaluronic acid. CD44, the main receptor for hyaluronic acid, and some of its splice variants are frequently overexpressed on cancer stem cells, including LSC. In this study we aimed to evaluate the in vivo anti-LSC activity of CD44 monoclonal antibody (mAb) RG7356. Methods and Results For anti-CD44 LSC inhibition studies, immunodeficient RAG2-/-γc-/- neonatal mice were intrahepatically transplanted with human BC LSC from imatinib responsive and resistant patients. Once engraf...
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Blood
1507 Leukemia initiating cells (LIC) contribute to therapeutic resistance as a result of their ca... more 1507 Leukemia initiating cells (LIC) contribute to therapeutic resistance as a result of their capacity to accumulate mutations in pathways, such as the NOTCH1 receptor signaling pathway, that promote self-renewal and survival within specific niches. Activating mutations in NOTCH1 occur commonly in T cell acute lymphoblastic leukemia (T-ALL) and have been implicated in driving therapeutic resistance. However, the role of NOTCH1 activation in human T-ALL LIC propagation and LIC sensitivity to selective NOTCH1 receptor inhibition has not been examined. The difficulties in maintaining primary cultures of leukemia cells have hampered investigations into the biology of T-ALL LIC and underscore the need for a direct transplantation model to characterize human LIC in vivo and as a paradigm for screening candidate drugs that inhibit self-renewal pathways active in T-ALL LIC. Pediatric T-ALL serially transplantable LIC were found to be enriched in the CD34+CD4− and CD34+CD7− fractions of new...
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Blood
Introduction Human bone marrow aging is typified by decreased cellularity, stem cell exhaustion a... more Introduction Human bone marrow aging is typified by decreased cellularity, stem cell exhaustion and myeloid lineage bias that may set the stage for development of myeloid malignancies. Secondary AML (sAML) arises from prior myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN), and occurs in patients with an average age of >65. Because of the typically advanced age of this population, patients currently have few effective treatment options available after leukemic transformation. We and others have recently identified a key role for enzymatic RNA editing activity in cancer progression, and in particular in leukemia stem cell (LSC) generation. In hematopoietic stem and progenitor cells, adenosine deaminase acting on dsRNA-1 (ADAR1) is the most abundantly expressed RNA editing gene. However, the role of abnormal RNA editing activity has not been elucidated in healthy human bone marrow aging and age-related MDS with a high risk of transforming to sAML. Therefore, we ...
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Blood
516 Introduction: Several studies have demonstrated the role of leukemia stem cells (LSC) in the ... more 516 Introduction: Several studies have demonstrated the role of leukemia stem cells (LSC) in the development and maintenance of human chronic myeloid leukemia (CML). These cells, which first develop in chronic phase CML (CP CML) with acquisition of the BCR-ABL fusion protein, are often quiescent and can be highly resistant to apoptosis induced by drugs and radiotherapy that target rapidly dividing cells. Data has also shown that CML LSC become increasingly resistant to BCR-ABL inhibition with progression to blast crisis CML (BC CML). Bcl-2 family proteins are key regulators of apoptosis and have been shown by numerous studies to regulate cancer resistance to chemotherapy. This family of proteins has also been implicated in the development of BC CML, however most studies have focused on CML cell lines and their expression of Bcl-2 family proteins in vitro. Thus, there is relatively little data on expression of Bcl-2 family proteins in primary CML LSC and on the role of these proteins...
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Blood
Introduction Disease relapse is the leading cause of death in secondary AML (sAML), which evolves... more Introduction Disease relapse is the leading cause of death in secondary AML (sAML), which evolves from antecedent hematologic disorders like myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPNs) or following exposure to chemotherapy. Persistence of therapy-resistant leukemia stem cells (LSC) harboring enhanced survival and self-renewal capacity has been linked to high relapse rates in sAML. Previously, we showed that missplicing of a stem cell regulatory gene, GSK3 b, and splice isoform switching favoring pro-survival BCL2 family isoform expression promoted generation of therapy-resistant LSC (Abrahamsson et al PNAS 2009; Goff et al Cell Stem Cell 2013). However, whether aberrant pre-mRNA splicing promotes sAML LSC generation, in the absence of mutation, and if pharmacological splicing modulation impairs LSC maintenance, in a mutation-independent manner, has not been elucidated. Methods and Results Comparative RNA-sequencing and gene set enrichment analyses revealed ...
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Blood
Introduction Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the... more Introduction Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the BCR-ABL fusion oncogene whose protein product has greatly increased ABL1 kinase activity. Although specific BCR-ABL tyrosine kinase inhibitors (TKIs) and the second generation TKIs like Nilotinib and the dual specific SCR and ABL inhibitor Dasatinib/Sprycel have dramatically improved CML therapy and significantly slowed disease progression by eradicating the bulk of CML cells in the circulation, they frequently fail to eliminate quiescent leukemic stem cells residing in the protective bone marrow niche. Leukemia stem cells (LSC) are able to drive disease relapse and may eventually contribute to the emergence of TKI resistant blast crisis (BC) CML, which is the final phase in the evolution of CML with rapid progression and short survival. CD44 is an adhesion molecule that promotes retention in the niche through adhesion to extracellular matrix components, such as hyaluron...
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Blood
Introduction Malignant reprogramming, first described in chronic myeloid leukemia (CML), occurs u... more Introduction Malignant reprogramming, first described in chronic myeloid leukemia (CML), occurs upon activation of the Wnt/b-catenin pathway in granulocyte-macrophage progenitors (GMPs) that gain the capacity to self-renew and contribute to the emergence of BCR-ABL1 tyrosine kinase inhibitor (TKI) resistant blast crisis CML. Deregulation of the Wnt/b-catenin target gene, CD44, plays a vital role in leukemia stem cell (LSC) maintenance in the malignant microenvironment in mouse models of CML. However, extensive alternative mRNA splicing in humans results in expression of multiple CD44 isoforms, some of which have been implicated in cancer invasion and metastasis. In this study we investigated the role of CD44 splice variant expression on human blast crisis LSC maintenance in the malignant niche. Methods and Results CD44 Isoform Expression Analysis To investigate the splice isoform expression pattern of CD44, whole transcriptome RNA sequencing (RNA Seq; Illumina HiSeq 2000) was perfor...
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Blood
1034 Introduction: T-cell acute lymphoblastic leukemia (T-ALL) is a therapeutically recalcitrant ... more 1034 Introduction: T-cell acute lymphoblastic leukemia (T-ALL) is a therapeutically recalcitrant malignancy that accounts for approximately 15% of pediatric and 25% of adult ALL cases. In leukemia, cancer stem cells constitute a relatively rare population of tumor cells that play a key role in cancer propagation and, like adult stem cells, have enhanced self-renewal potential. A previous report showed that following in vitro culture, CD34+/CD4- and CD34+/CD7- subfractions of T-ALL marrow were enriched for leukemia stem cells (LSC) capable of engrafting leukemia in nonobese diabetic/severe combined immune deficient mouse (NOD/SCID). However, difficulties in maintaining primary cultures of leukemia cells hampered investigations into the biology of T-ALL underscoring the need for a direct transplantation model to characterize human LSC in vivo and as a paradigm for screening candidate drugs that inhibit self-renewal pathways active in T-ALL. Experimental Procedures: Quantitative RT-PCR...
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Blood
910 In blast crisis transformation of CML (BC CML), the leukemia stem cells (LSC), via the acquis... more 910 In blast crisis transformation of CML (BC CML), the leukemia stem cells (LSC), via the acquisition of both enhanced survival and self-renewal capacity, become increasingly resistant to BCR-ABL targeted tyrosine kinase inhibition and thus often contribute to relapse after treatment, pointing to the need for alternative therapeutic strategies and a better understanding of the molecular mechanisms underlying disease progression. Janus kinase 2 (JAK2) plays an important role in BCR–ABL + cell survival and has profound effects on self-renewal and lineage commitment of normal and leukemic hematopoietic stem cells, through the activation of the transcription factor signal transducer and activator of transcription 5 (STAT5). To determine if JAK/STAT signaling pathway activation is related to CML progression, LSC from human Chronic Phase (CP CML) and BC CML samples were sorted using FACS Aria (Lin-CD34+CD38+) and analyzed using splice-isoform specific q-RT-PCR. Our results showed that, c...
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Blood
3739 Leukemia stem cells (LSC) represent a frequently dormant self-renewing population integral t... more 3739 Leukemia stem cells (LSC) represent a frequently dormant self-renewing population integral to the initiation, maintenance, and progression of human chromic myeloid leukemia (CML). The current standard of care dasatinib, a BCR-ABL targeted tyrosine kinase inhibitor (TKI), effectively eradicates the bulk of CML cells but frequently fails to affect the LSC population that is thought to drive CML relapse. Members in the BCL2 family are proteins that regulate apoptosis, 6 of which regulate cell survival. Each of these 6 members has a long and short isoform with opposing functions; generally, long isoforms promote cell survival while the short isoforms promote apoptosis. Previously, we demonstrated that upregulation of pro-survival BCL2 proteins in CML LSC contributes to chemotherapy resistance and LSC quiescence in protective hematopoietic niches. LSC found in different hematopoietic niches differ in their response to TKI treatment. Niche affects LSC cell cycle, either by maintainin...
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Cell Stem Cell, 2016
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Papers by Anil Sadarangani