Publications by authors named "Sandeep Potluri"

7 Publications

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Isoform-specific and signaling-dependent propagation of acute myeloid leukemia by Wilms tumor 1.

Cell Rep 2021 Apr;35(3):109010

Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B152TT, UK. Electronic address:

Acute myeloid leukemia (AML) is caused by recurrent mutations in members of the gene regulatory and signaling machinery that control hematopoietic progenitor cell growth and differentiation. Here, we show that the transcription factor WT1 forms a major node in the rewired mutation-specific gene regulatory networks of multiple AML subtypes. WT1 is frequently either mutated or upregulated in AML, and its expression is predictive for relapse. The WT1 protein exists as multiple isoforms. For two main AML subtypes, we demonstrate that these isoforms exhibit differential patterns of binding and support contrasting biological activities, including enhanced proliferation. We also show that WT1 responds to oncogenic signaling and is part of a signaling-responsive transcription factor hub that controls AML growth. WT1 therefore plays a central and widespread role in AML biology.
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http://dx.doi.org/10.1016/j.celrep.2021.109010DOI Listing
April 2021

Subtype-specific regulatory network rewiring in acute myeloid leukemia.

Nat Genet 2019 01 12;51(1):151-162. Epub 2018 Nov 12.

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.

Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype-specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of subjects carrying mutations in genes encoding transcription factors (RUNX1, CEBPα), signaling molecules (FTL3-ITD, RAS) and the nuclear protein NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance.
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http://dx.doi.org/10.1038/s41588-018-0270-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330064PMC
January 2019

Pharmacological inhibition of aberrant transcription factor complexes in inversion 16 acute myeloid leukemia.

Stem Cell Investig 2018 30;5:30. Epub 2018 Sep 30.

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.

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http://dx.doi.org/10.21037/sci.2018.09.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182015PMC
September 2018

The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation.

Cancer Cell 2018 10;34(4):626-642.e8

Institute for Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK. Electronic address:

Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML.
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http://dx.doi.org/10.1016/j.ccell.2018.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179967PMC
October 2018

Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies.

Blood 2011 Apr 4;117(17):4519-29. Epub 2011 Mar 4.

Targeted Therapy Group, Paterson Institute for Cancer Research, School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic Health Sciences Center, Manchester, UK.

The anti-CD20 mAb rituximab has substantially improved the clinical outcome of patients with a wide range of B-cell malignancies. However, many patients relapse or fail to respond to rituximab, and thus there is intense investigation into the development of novel anti-CD20 mAbs with improved therapeutic efficacy. Although Fc-FcγR interactions appear to underlie much of the therapeutic success with rituximab, certain type II anti-CD20 mAbs efficiently induce programmed cell death (PCD), whereas rituximab-like type I anti-CD20 mAbs do not. Here, we show that the humanized, glycoengineered anti-CD20 mAb GA101 and derivatives harboring non-glycoengineered Fc regions are type II mAb that trigger nonapoptotic PCD in a range of B-lymphoma cell lines and primary B-cell malignancies. We demonstrate that GA101-induced cell death is dependent on actin reorganization, can be abrogated by inhibitors of actin polymerization, and is independent of BCL-2 overexpression and caspase activation. GA101-induced PCD is executed by lysosomes which disperse their contents into the cytoplasm and surrounding environment. Taken together, these findings reveal that GA101 is able to potently elicit actin-dependent, lysosomal cell death, which may potentially lead to improved clearance of B-cell malignancies in vivo.
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http://dx.doi.org/10.1182/blood-2010-07-296913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3099571PMC
April 2011