Browsing by Subject "Leukemia"

Now showing 1 - 10 of 31
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    Age is no barrier for adults undergoing HCT for AML in CR1: contemporary CIBMTR analysis
    (Springer Nature, 2022) Maakaron, Joseph E.; Zhang, Mei-Jie; Chen, Karen; Abhyankar, Sunil; Bhatt, Vijaya Raj; Chhabra, Saurabh; El Jurdi, Najla; Farag, Sherif S.; He, Fiona; Juckett, Mark; de Lima, Marcos; Majhail, Navneet; van der Poel, Marjolein; Saad, Ayman; Savani, Bipin; Ustun, Celalettin; Waller, Edmund K.; Litzow, Mark; Kebriaei, Partow; Hourigan, Christopher S.; Saber, Wael; Weisdorf, Daniel; Medicine, School of Medicine
    Acute Myeloid Leukemia (AML) has a median age at diagnosis of 67 years. The most common curative therapy remains an allogeneic hematopoietic stem cell transplantation (HCT), yet it is complicated by treatment-related mortality (TRM) and ongoing morbidity including graft versus host disease (GVHD) that may impact survival, particularly in older patients. We examined the outcomes and predictors of success in 1321 patients aged 60 years and older receiving a HCT for AML in first complete remission (CR1) from 2007-2017 and reported to the CIBMTR. Outcomes were compared in three age cohorts (60-64; 65-69; 70+). With median follow-up of nearly 3 years, patients aged 60-64 had modestly, though significantly better OS, DFS and lower TRM than those either 65-69 or 70+; cohorts with similar outcomes. Three-year OS for the 3 cohorts was 49.4%, 42.3%, and 44.7% respectively (p = 0.026). TRM was higher with increasing age, cord blood as graft source and HCT-CI score of ≥3. Conditioning intensity was not a significant predictor of OS in the 60-69 cohort with 3-year OS of 46% for RIC and 49% for MAC (p = 0.38); MAC was rarely used over age 70. There was no difference in the relapse rate, incidence of Grade III/IV acute GVHD, or moderate-severe chronic GVHD across the age cohorts. After adjusting for other predictors, age had a small effect on OS and TRM. High-risk features including poor cytogenetics and measurable residual disease (MRD) prior to HCT were each significantly associated with relapse and accounted for most of the adverse impact on OS and DFS. Age did not influence the incidence of either acute or chronic GVHD; while graft type and associated GVHD prophylaxis were most important. These data suggest that age alone is not a barrier to successful HCT for AML in CR1 and should not exclude patients from HCT. Efforts should focus on minimizing residual disease and better donor selection.
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    AUCTSP: an improved biomarker gene pair class predictor
    (BMC, 2018-06-26) Kagaris, Dimitri; Khamesipour, Alireza; Yiannoutsos, Constantin T.; Biostatistics, School of Public Health
    The Top Scoring Pair (TSP) classifier, based on the concept of relative ranking reversals in the expressions of pairs of genes, has been proposed as a simple, accurate, and easily interpretable decision rule for classification and class prediction of gene expression profiles. The idea that differences in gene expression ranking are associated with presence or absence of disease is compelling and has strong biological plausibility. Nevertheless, the TSP formulation ignores significant available information which can improve classification accuracy and is vulnerable to selecting genes which do not have differential expression in the two conditions ("pivot" genes). RESULTS: We introduce the AUCTSP classifier as an alternative rank-based estimator of the magnitude of the ranking reversals involved in the original TSP. The proposed estimator is based on the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) and as such, takes into account the separation of the entire distribution of gene expression levels in gene pairs under the conditions considered, as opposed to comparing gene rankings within individual subjects as in the original TSP formulation. Through extensive simulations and case studies involving classification in ovarian, leukemia, colon, breast and prostate cancers and diffuse large b-cell lymphoma, we show the superiority of the proposed approach in terms of improving classification accuracy, avoiding overfitting and being less prone to selecting non-informative (pivot) genes. CONCLUSIONS: The proposed AUCTSP is a simple yet reliable and robust rank-based classifier for gene expression classification. While the AUCTSP works by the same principle as TSP, its ability to determine the top scoring gene pair based on the relative rankings of two marker genes across all subjects as opposed to each individual subject results in significant performance gains in classification accuracy. In addition, the proposed method tends to avoid selection of non-informative (pivot) genes as members of the top-scoring pair.
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    Cancer outcomes among Parkinson's disease patients with leucine rich repeat kinase 2 mutations, idiopathic Parkinson's disease patients, and nonaffected controls
    (Wiley, 2019-09) Agalliu, llir; Ortega, Roberto A.; San Luciano, Marta; Mirelman, Anat; Pont-Sunyer, Claustre; Brockmann, Kathrin; Vilas, Dolores; Tolosa, Eduardo; Berg, Daniela; Warø, Bjørg; Glickman, Amanda; Raymond, Deborah; Inzelberg, Rivka; Ruiz-Martinez, Javier; Mondragon, Elisabet; Friedman, Eitan; Hassin-Baer, Sharon; Alcalay, Roy N.; Mejia-Santana, Helen; Aasly, Jan; Foroud, Tatiana; Marder, Karen; Giladi, Nir; Bressman, Susan; Saunders-Pullman, Rachel; Medical and Molecular Genetics, School of Medicine
    BACKGROUND: Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls. METHODS: Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients. RESULTS: Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients. CONCLUSIONS: The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society.
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    Cellular FLICE-like inhibitory protein (C-FLIP): a novel target for cancer therapy
    (Bentham Science, 2008-02) Safa, Ahmad R.; Day, Travis W.; Wu, Ching-Huang; Department of Pharmacology and Toxicology, IU School of Medicine
    Cellular FLICE-like inhibitory protein (c-FLIP) has been identified as a protease-dead, procaspase-8-like regulator of death ligand-induced apoptosis, based on observations that c-FLIP impedes tumor necrosis factor-alpha (TNF-alpha), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by binding to FADD and/or caspase-8 or -10 in a ligand-dependent fashion, which in turn prevents death-inducing signaling complex (DISC) formation and subsequent activation of the caspase cascade. c-FLIP is a family of alternatively spliced variants, and primarily exists as long (c-FLIP(L)) and short (c-FLIP(S)) splice variants in human cells. Although c-FLIP has apoptogenic activity in some cell contexts, which is currently attributed to heterodimerization with caspase-8 at the DISC, accumulating evidence indicates an anti-apoptotic role for c-FLIP in various types of human cancers. For example, small interfering RNAs (siRNAs) that specifically knocked down expression of c-FLIP(L) in diverse human cancer cell lines, e.g., lung and cervical cancer cells, augmented TRAIL-induced DISC recruitment, and thereby enhanced effector caspase stimulation and apoptosis. Therefore, the outlook for the therapeutic index of c-FLIP-targeted drugs appears excellent, not only from the efficacy observed in experimental models of cancer therapy, but also because the current understanding of dual c-FLIP action in normal tissues supports the notion that c-FLIP-targeted cancer therapy will be well tolerated. Interestingly, Taxol, TRAIL, as well as several classes of small molecules induce c-FLIP downregulation in neoplastic cells. Efforts are underway to develop small-molecule drugs that induce c-FLIP downregulation and other c-FLIP-targeted cancer therapies. In this review, we assess the outlook for improving cancer therapy through c-FLIP-targeted therapeutics.
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    Crystal structures of oligonucleotides including the integrase processing site of the Moloney murine leukemia virus
    (Oxford University Press, 2006-11-01) Montaño, Sherwin P.; Cote, Marie L.; Roth, Monica J.; Georgiadis, Millie M.; Biochemistry and Molecular Biology, School of Medicine
    In the first step of retroviral integration, integrase cleaves the linear viral DNA within its long terminal repeat (LTR) immediately 3′ to the CA dinucleotide step, resulting in a reactive 3′ OH on one strand and a 5′ two base overhang on the complementary strand. In order to investigate the structural properties of the 3′ end processing site within the Moloney murine leukemia virus (MMLV) LTR d(TCTTTCATT), a host-guest crystallographic method was employed to determine the structures of four self-complementary 16 bp oligonucleotides including LTR sequences (underlined), d(TTTCATTGCAATGAAA), d(CTTTCATTAATGAAAG), d(TCTTTCATATGAAAGA) and d(CACAATGATCATTGTG), the guests, complexed with the N-terminal fragment of MMLV reverse transcriptase, the host. The structures of the LTR-containing oligonucleotides were compared to those of non-LTR oligonucleotides crystallized in the same lattice. Properties unique to the CA dinucleotide step within the LTR sequence, independent of its position from the end of the duplex, include a positive roll angle and negative slide value. This propensity for the CA dinucleotide step within the MMLV LTR sequence to adopt only positive roll angles is likely influenced by the more rigid, invariable 3′ and 5′ flanking TT dinucleotide steps and may be important for specific recognition and/or cleavage by the MMLV integrase.
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    DNA Damage On The DOCK In FLT3-ITD-Driven Acute Myeloid Leukemia
    (Ferrata Storti Foundation, 2019-12) Pandey, Ruchi; Kapur, Reuben; Pediatrics, School of Medicine
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    Drug-drug similarity networks for anti-cancer drug discovery – Case studies on Breast Cancer, Colorectal Cancer and Leukemia
    (Office of the Vice Chancellor for Research, 2013-04-05) Kugbe, Selom; Grinslade, Zachary; Momoh, Salamatu; Ibrahim, Sara
    Over the decades, the medical industry has been challenged with the issue of producing drugs that would avoid sidetracking to other targets (off-targets) and keep away from harmful side effects (drug adverse reactions). Many researches have shown that complex diseases, such as various cancers, make the “one disease - one target - one drug” strategy unsuccessful due to the intrinsic complexity of gene-gene interactions and gene-environment interactions. In order to discover efficient treatments for these diseases, we assume that optimal drugs should be capable of down-regulating the effects of over-expressed genes while activating the under-expressed genes, when necessary, to restore the patient’s status to a healthy one. In this MURI project, we constructed drug-drug similarity network models, as two drugs having similar side effects, targets or chemical structures may have compatible therapeutic effects on the diseases. First, we retrieved a list of top-ranking drugs for specific disease (using Breast Cancer, Colorectal Cancer and Leukemia as case studies) from different data sources of connection maps, including the CMaps webserver. Second, we identified the protein targets for each drugs using databases such as PubChem, MataDor, MetaDrug, the European Bioinformaics Institute, and DrugBank. Third, we calculated similarities between two drugs by using different types of definitions based on their characteristics, such as shared targets, chemical structures, ontology and side effects. Finally, a comprehensive drug-drug similarity network with multiple similarity definitions was created for each disease, through a molecular network visualization platform - Cytoscape. These drug-drug similarity networks for specific cancer phenotypes can be applied to the validation of therapeutic effect assessment for specific anti-cancer drugs based on drug-protein networks. Our research highlights the importance of drug similarity analysis, and will eventually help anti-cancer drug discovery in silico.
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    Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation
    (MDPI, 2024-03-16) Chen, Can; Zhang, Ji; Pediatrics, School of Medicine
    Cancer cells demand amino acids beyond their usage as "building blocks" for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged as a pivotal strategy in cancer treatment. In the setting of leukemia therapy, compelling examples of targeting amino acid metabolism exist at both pre-clinical and clinical stages. This review focuses on summarizing novel insights into the metabolism of glutamine, asparagine, arginine, and tryptophan in leukemias, and providing a comprehensive discussion of perturbing their metabolism to improve the therapeutic outcomes. Certain amino acids, such as glutamine, play a vital role in the energy metabolism of cancer cells and the maintenance of redox balance, while others, such as arginine and tryptophan, contribute significantly to the immune microenvironment. Therefore, assessing the efficacy of targeting amino acid metabolism requires comprehensive strategies. Combining traditional chemotherapeutics with novel strategies to perturb amino acid metabolism is another way to improve the outcome in leukemia patients via overcoming chemo-resistance or promoting immunotherapy. In this review, we also discuss several ongoing or complete clinical trials, in which targeting amino acid metabolism is combined with other chemotherapeutics in treating leukemia.
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    Erk1 and Erk2 in hematopoiesis, mast cell function, and the management of Nf1-associated leukemia and tumors
    (2012-03) Staser, Karl W.; Clapp, D. Wade; Yang, Feng-Chun; Goebl, Mark, 1958-; Harrington, Maureen A.
    Neurofibromatosis type 1 is a genetic disease that results from either heritable or spontaneous autosomal dominant mutations in the NF1 gene, which encodes a protein serving, at least in part, to accelerate the intrinsic hydrolysis of active Ras-GTP to inactive Ras-GDP. A second-hit NF1 mutation precedes predominant NF1 neoplasms, including juvenile myelomoncytic leukemia (JMML) and plexiform neurofibroma formation, potentially fatal conditions with no medical therapy. While NF1 loss of heterozygosity (LOH) in myeloid progenitor cells sufficiently engenders leukemogenesis, plexiform neurofibroma formation depends on LOH in Schwann cells and Nf1 heterozygosity in the hematopoietic system. Specifically, recruited Nf1+/- mast cells accelerate tumorigenesis through secreted cytokines and growth factors. Nf1+/- mast cells depend upon deregulated signaling in c-kit pathways, a receptor system conserved in hematopoietic stem cells (HSCs). Accordingly, Nf1-/- myeloid progenitor cells, which can induce a JMML-like disease in mice, also demonstrate deregulated c-kit receptor signaling. C-kit-activated Nf1+/- mast cells and Nf1-/- myeloid progenitors both show increased latency and potency of active Erk1 and Erk2, the principal cytosolic-to-nuclear effectors of canonical Ras-Raf-Mek signaling. Thus, Erk represents a potential regulator of leukemogenesis and tumor-associated inflammation. However, single and combined Erk1 and Erk2 roles in HSC function, myelopoiesis, and mature mast cell physiology remain unknown, and recent hematopoietic studies relying on chemical Mek-Erk inhibitors have produced conflicting results. Here, we show that hematopoietic stability, myelopoiesis, and mast cell generation require Erk1 or Erk2, but individual isoforms are largely dispensable. Principally, Erk-disrupted hematopoietic stem cells incorporate BrdU but are incapable of dividing, a novel and cell type-specific Erk function. Similarly, mast cell proliferation requires Erk but cytokine production proceeds through other pathways, elucidating molecule-specific functions within the c-kit cascade. Based on these findings, we have reduced tumor mast cell infiltration by treating genetically-engineered tumor model mice with PD0325901, a preclinical Mek-Erk inhibitor. Moreover, we have devised a quadruple transgenic HSC transplantation model to examine dual Erk disruption in the context of Nf1 nullizygosity, testing whether diseased hematopoiesis requires Erk. These insights illuminate cell-specific Erk functions in normal and Nf1-deficient hematopoiesis, informing the feasibility of targeting Mek-Erk in NF1-associated disease.