Computational modeling of early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) to identify personalized therapy using genomics

Kumar, Ansu; Drusbosky, Leylah; Meacham, Amy; Turcotte, Madeleine; Bhargav, Priyanka; Vasista, Sumanth; Usmani, Shahabuddin; Pampana, Anusha; Basu, Kabya; Tyagi, Anuj; Lala, Deepak Anil; Rajagopalan, Swaminathan; Birajdar, Shivgonda; Alam, Aftab; Roy, Kaushik; Abbasi, Taher; Vali, Shireen; Sengar, Manju; Chinnaswamy, Girish; Shah, Bijal; Cogle, Christopher R.

doi:10.1016/j.leukres.2019.01.003

Cited by 9 publications

(10 citation statements)

References 30 publications

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“… 12 – 15 Recently, NPM1 deletions were found to be enriched in ETP-ALL patients. 16 The ETP-ALL cases reported in the literature do not have a uniform or pathognomonic cytogenetic aberration profile. PICALM-MLLT10 fusion has been reported and was associated with dismal prognosis in the context of ETP-ALL.…”

Section: Etp-all: a Distinct Entity Of T-cell Allmentioning

confidence: 98%

“…A recent publication utilized computational biology modeling to identify synergistic chemotherapy combinations for patients with ETP-ALL. 16 In addition, ex vivo models were able to identify the sensitivity of ETP-ALL cells to venetoclax and other compounds. 86,88 In another publication, patient derived xenotransplants were used to identify tyrosine phosphorylation pattern.…”

Section: Novel Treatment and Approachesmentioning

confidence: 99%

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Early precursor T-cell acute lymphoblastic leukemia: current paradigms and evolving concepts

Puglianini

Papadantonakis

2020

Therapeutic Advances in Hematology

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Section: Etp-all: a Distinct Entity Of T-cell Allmentioning

confidence: 98%

Section: Novel Treatment and Approachesmentioning

confidence: 99%

Early precursor T-cell acute lymphoblastic leukemia: current paradigms and evolving concepts

Puglianini

Papadantonakis

2020

Therapeutic Advances in Hematology

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“…The leukemic cells derive from immature thymocytes that retain stem cell and myeloid lineage characteristics. Defects in transcriptional factors LMO2, LYL1, and HOXA and mutations in IKZF1 and MED12 and rearrangement of NUP98 as well as myeloid malignancy mutations such as FLT3 , WT1 , EZH2 , RAS , RUNX1, and NPM1 are also seen [ 23 , 46 , 74 , 75 , 76 ]. In the GRAALL-2003 and -2005 studies, HOXA overexpression was associated with poor prognosis in adults with ETP-ALL.…”

Section: Immunophenotypic Classificationmentioning

confidence: 99%

T-Cell Acute Lymphoblastic Leukemia—Current Concepts in Molecular Biology and Management

2021

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T-cell acute lymphoblastic leukemia (T-ALL) is an uncommon, yet aggressive leukemia that accounts for approximately one-fourth of acute lymphoblastic leukemia (ALL) cases. CDKN2A/CDKN2B and NOTCH1 are the most common mutated genes in T-ALL. Children and young adults are treated with pediatric intensive regimens and have superior outcomes compared to older adults. In children and young adults, Nelarabine added to frontline chemotherapy improves outcomes and end of consolidation measurable residual disease has emerged as the most valuable prognostic marker. While outcomes for de-novo disease are steadily improving, patients with relapsed and refractory T-ALL fare poorly. Newer targeted therapies are being studied in large clinical trials and have the potential to further improve outcomes. The role of allogeneic stem cell transplant (HSCT) is evolving due to the increased use of pediatric-inspired regimens and MRD monitoring. In this review we will discuss the biology, treatment, and outcomes in pediatric and adult T-ALL.

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“…HDAC blockade unchains PPARγ-mediated anti-proliferative and anti-angiogenic signaling Because PPARγ has an extensive repertoire of downstream target genes while HDAC1/2 alters chromatin accessibility and gene expression on a genome-wide scale, pharmacological modulation of these pleiotropic regulators of gene transcription would invariably perturb a myriad of biological pathways simultaneously. To sieve out anticancer mechanisms efficiently, we began by conducting in silico simulations using a validated systems pharmacology model [28][29][30][31][32][33][34][35][36][37][38] (Supplementary Results: Part S3). We then validated these bioinformatics predictions through RT-qPCR and in vitro angiogenesis assays (Supplementary Results: Part S3).…”

Section: Hdac Inhibition Enhances Pparγ Expression Acetylation and Ppre Activitymentioning

confidence: 99%

Epigenetic derepression converts PPARγ into a druggable target in triple-negative and endocrine-resistant breast cancers

et al. 2021

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Clinical trials repurposing peroxisome proliferator-activated receptor-gamma (PPARγ) agonists as anticancer agents have exhibited lackluster efficacy across a variety of tumor types. Here, we report that increased PPARG expression is associated with a better prognosis but is anticorrelated with histone deacetylase (HDAC) 1 and 2 expressions. We show that HDAC overexpression blunts anti-proliferative and anti-angiogenic responses to PPARγ agonists via transcriptional and post-translational mechanisms, however, these can be neutralized with clinically approved and experimental HDAC inhibitors. Supporting this notion, concomitant treatment with HDAC inhibitors was required to license the tumor-suppressive effects of PPARγ agonists in triple-negative and endocrine-refractory breast cancer cells, and combination therapy also restrained angiogenesis in a tube formation assay. This combination was also synergistic in estrogen receptor-alpha (ERα)–positive cells because HDAC blockade abrogated ERα interference with PPARγ-regulated transcription. Following a pharmacokinetics optimization study, the combination of rosiglitazone and a potent pan-HDAC inhibitor, LBH589, stalled disease progression in a mouse model of triple-negative breast cancer greater than either of the monotherapies, while exhibiting a favorable safety profile. Our findings account for historical observations of de-novo resistance to PPARγ agonist monotherapy and propound a therapeutically cogent intervention against two aggressive breast cancer subtypes.

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Computational modeling of early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) to identify personalized therapy using genomics

Cited by 9 publications

References 30 publications

Early precursor T-cell acute lymphoblastic leukemia: current paradigms and evolving concepts

Early precursor T-cell acute lymphoblastic leukemia: current paradigms and evolving concepts

T-Cell Acute Lymphoblastic Leukemia—Current Concepts in Molecular Biology and Management

Epigenetic derepression converts PPARγ into a druggable target in triple-negative and endocrine-resistant breast cancers

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