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Full-Text Articles in Cancer Biology

Characterization Of A More Clinically Relevant Human Leukemia Xenograft Model To Examine Perturbation Of Met/Sam Metabolism As A Novel Therapeutic Paradigm For Mll-R Leukemia In Vivo., Aditya Barve Aug 2019

Characterization Of A More Clinically Relevant Human Leukemia Xenograft Model To Examine Perturbation Of Met/Sam Metabolism As A Novel Therapeutic Paradigm For Mll-R Leukemia In Vivo., Aditya Barve

Electronic Theses and Dissertations

Acute myeloid leukemia (AML), is a heterogeneous clonal disorder characterized by an accumulation of malignant myeloid progenitors in the bone marrow (BM), hindering normal hematopoiesis. AML exhibits dramatic heterogeneity in terms of cytogenetics, morphology, and chemotherapeutic sensitivity. Therefore, the investigation of novel, efficacious AML therapeutics will require advanced preclinical in vivo model systems, capable of recapitulating patient specific disease heterogeneity, and induction chemotherapy outcomes. A major focus and eventual outcome of this work was the establishment and development of a more clinically relevant mouse xenograft model of patient AML, that efficiently harbors patient derived xenografts (PDXs), and unlike more prevalent ...


Exploiting Unique Biological Features Of Leukemia Stem Cells For Therapeutic Benefit, Haojian Zhang, Shaoguang Li Apr 2019

Exploiting Unique Biological Features Of Leukemia Stem Cells For Therapeutic Benefit, Haojian Zhang, Shaoguang Li

Open Access Articles

Cancer stem cells play a critical role in disease initiation and insensitivity to chemotherapy in numerous hematologic malignancies and some solid tumors, and these stem cells need to be eradicated to achieve a cure. Key to successful targeting of cancer stem cells is to identify and functionally test critical target genes and to fully understand their associated molecular network in these stem cells. Human chronic myeloid leukemia (CML) is well accepted as one of the typical types of hematopoietic malignancies that are derived from leukemia stem cells (LSCs), serving as an excellent model disease for understanding the biology of LSCs ...


Trim24 In Normal & Malignant Hematopoiesis, Justin Shaw May 2018

Trim24 In Normal & Malignant Hematopoiesis, Justin Shaw

UT GSBS Dissertations and Theses (Open Access)

Treatment for acute myeloid leukemia (AML) has changed little in the past four decades. For the majority of AML patients, current treatment options include chemotherapy and allogeneic stem cell transplants, which also involves high-dose chemotherapy or radiation treatment. These options have little success in the long-run, as only an estimated 26% of patients survive five years post-diagnosis. In efforts to address this low survival rate, interest has increased for targeting epigenetic pathways in AML. This focus stems from the discovery that AML is frequently driven by blockades on hematopoietic stem cell differentiation, which involves a series of coordinated epigenetic changes ...


Preleukemia And Leukemia-Initiating Cell Activity In Inv(16) Acute Myeloid Leukemia, John A. Pulikkan, Lucio H. Castilla Apr 2018

Preleukemia And Leukemia-Initiating Cell Activity In Inv(16) Acute Myeloid Leukemia, John A. Pulikkan, Lucio H. Castilla

Open Access Articles

Acute myeloid leukemia (AML) is a collection of hematologic malignancies with specific driver mutations that direct the pathology of the disease. The understanding of the origin and function of these mutations at early stages of transformation is critical to understand the etiology of the disease and for the design of effective therapies. The chromosome inversion inv(16) is thought to arise as a founding mutation in a hematopoietic stem cell (HSC) to produce preleukemic HSCs (preL-HSCs) with myeloid bias and differentiation block, and predisposed to AML. Studies in mice and human AML cells have established that inv(16) AML follows ...


Defining A Therapeutic Window For Kinase Inhibitors In Leukemia To Avoid Neutropenia, Kate Mcarthur, Akshay A. D'Cruz, David Segal, Kurt Lackovic, Andrew F. Wilks, Joanne A. O'Donnell, Cameron J. Nowell, Motti Gerlic, David C. S. Huang, Christopher J. Burns, Ben A. Croker Jul 2017

Defining A Therapeutic Window For Kinase Inhibitors In Leukemia To Avoid Neutropenia, Kate Mcarthur, Akshay A. D'Cruz, David Segal, Kurt Lackovic, Andrew F. Wilks, Joanne A. O'Donnell, Cameron J. Nowell, Motti Gerlic, David C. S. Huang, Christopher J. Burns, Ben A. Croker

Open Access Articles

Neutropenia represents one of the major dose-limiting toxicities of many current cancer therapies. To circumvent the off-target effects of cytotoxic chemotherapeutics, kinase inhibitors are increasingly being used as an adjunct therapy to target leukemia. In this study, we conducted a screen of leukemic cell lines in parallel with primary neutrophils to identify kinase inhibitors with the capacity to induce apoptosis of myeloid and lymphoid cell lines whilst sparing primary mouse and human neutrophils. We have utilized a high-throughput live cell imaging platform to demonstrate that cytotoxic drugs have limited effects on neutrophil viability but are toxic to hematopoietic progenitor cells ...


Cd82 Membrane Scaffolding Regulates Hematopoietic Cell Functions, Christina M. Termini May 2017

Cd82 Membrane Scaffolding Regulates Hematopoietic Cell Functions, Christina M. Termini

Biomedical Sciences ETDs

Through their ability to self-renew and differentiate, hematopoietic stem/progenitor cells (HSPCs) maintain the adult blood and immune systems. The microenvironment, or niche, in which HSPCs reside, serves as a critical regulator of HSPC functions. As previous work has identified the tetraspanin CD82 as a mediator of HSPC-niche interactions, we aimed to determine the mechanism by which this occurs. Our data demonstrate that CD82 expression and scaffolding regulate HSPC interactions with niche components by organizing the α4 integrin subunit into tightly packed nanoclusters. The HSPC niche can also protect acute myeloid leukemia (AML) cells from therapeutics. Therefore, we next examined ...


Mechanism Of Lck Activation In Driving Leukemia Cell Proliferation, Hannah E. Dobson May 2017

Mechanism Of Lck Activation In Driving Leukemia Cell Proliferation, Hannah E. Dobson

Senior Honors Projects

Leukemia is a type of cancer that develops in blood-forming tissues of the immune system. These tissues can include the bone marrow or sites within the lymphatic system such as the lymph nodes. Leukemia progresses from a mutational event within a white blood cell. Often this mutation alters the cell’s normal life cycle, resulting in uninhibited cell division and growth. With this uncontrolled cell proliferation, mutated white blood cells accumulate and begin interfering with the functioning of healthy cells.

Scientists are unsure of the exact mechanisms required for leukemia development. However, recently scientists identified four characteristic mutations in the ...


Small Molecule Inhibitor Of Cbfbeta-Runx Binding For Runx Transcription Factor Driven Cancers, Anuradha Illendula, John A. Pulikkan, Lucio H. Castilla, John H. Bushweller Jun 2016

Small Molecule Inhibitor Of Cbfbeta-Runx Binding For Runx Transcription Factor Driven Cancers, Anuradha Illendula, John A. Pulikkan, Lucio H. Castilla, John H. Bushweller

Open Access Articles

Transcription factors have traditionally been viewed with skepticism as viable drug targets, but they offer the potential for completely novel mechanisms of action that could more effectively address the stem cell like properties, such as self-renewal and chemo-resistance, that lead to the failure of traditional chemotherapy approaches. Core binding factor is a heterodimeric transcription factor comprised of one of 3 RUNX proteins (RUNX1-3) and a CBFbeta binding partner. CBFbeta enhances DNA binding of RUNX subunits by relieving auto-inhibition. Both RUNX1 and CBFbeta are frequently mutated in human leukemia. More recently, RUNX proteins have been shown to be key players in ...


T-Cell Treatments For Solid And Hematological Tumors, Drew C. Deniger Aug 2013

T-Cell Treatments For Solid And Hematological Tumors, Drew C. Deniger

UT GSBS Dissertations and Theses (Open Access)

Cell-based therapies have demonstrated potency and efficacy as cancer treatment modalities. T cells can be dichotomized by their T cell receptor (TCR) complexes where alpha/beta T cells (95% of T cells) and gamma/delta T cells (+T cells proliferated to clinically significant numbers and ROR1+ tumor cells were effectively targeted and killed by both ROR1-specific CAR+ T cell populations, although ROR1RCD137 were superior to ROR1RCD28 in clearance of leukemia xenografts in vivo. The second specific aim focused on generating bi-specific CD19-specific CAR+ gamma/delta T cells with polyclonal TCRgamma/delta repertoire on CD19+ artificial antigen presenting cells (aAPC). Enhanced ...


Oxidative Stress Based Strategies For Enhancing The Efficacy Of Histone Deacetylase Inhibitors (Hdaci), Nilsa Rivera-Del Valle May 2013

Oxidative Stress Based Strategies For Enhancing The Efficacy Of Histone Deacetylase Inhibitors (Hdaci), Nilsa Rivera-Del Valle

UT GSBS Dissertations and Theses (Open Access)

Histone deacetylase inhibitors (HDACi) are anti-cancer drugs that primarily act upon acetylation of histones, however they also increase levels of intracellular reactive oxygen species (ROS). We hypothesized that agents that cause oxidative stress might enhance the efficacy of HDACi. To test this hypothesis, we treated acute lymphocytic leukemia cells (ALL) with HDACi and adaphostin (ROS generating agent). The combination of two different HDACi (vorinostat or entinostat) with adaphostin synergistically induced apoptosis in ALL. This synergistic effect was blocked when cells were pre-treated with the caspase-9 inhibitor, LEHD. In addition, we showed that loss of the mitochondrial membrane potential is the ...


The Molecular Mechanisms For Maintenance Of Cancer Stem Cells In Chronic Myeloid Leukemia: A Dissertation, Haojian Zhang May 2012

The Molecular Mechanisms For Maintenance Of Cancer Stem Cells In Chronic Myeloid Leukemia: A Dissertation, Haojian Zhang

GSBS Dissertations and Theses

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder associated with the Philadelphia chromosome (Ph) that arises from a reciprocal translocation between chromosomes 9 and 22, thereby resulting in the formation of the chimeric BCR-ABL oncogene encoding a constitutively activated tyrosine kinase. BCR-ABL tyrosine kinase inhibitors (TKIs) induce a complete hematologic and cytogenetic response in the majority of chronic phrase CML patients. However, TKIs cannot efficiently eradicate leukemia stem cells (LSCs) because of the insensitivity of LSCs to TKIs. Therefore, developing new strategies to target LSCs is necessary and critical for curing CML, and success of this approach ...


Critical Molecular Pathways In Cancer Stem Cells Of Chronic Myeloid Leukemia: A Dissertation, Yaoyu Chen May 2011

Critical Molecular Pathways In Cancer Stem Cells Of Chronic Myeloid Leukemia: A Dissertation, Yaoyu Chen

GSBS Dissertations and Theses

Chronic myeloid leukemia (CML) is a disease characterized by the expansion of granulocytic cells. The BCR-ABL tyrosine kinase inhibitor imatinib, the frontline treatment for Ph+ leukemias, can induce complete hematologic and cytogenetic response in most chronic phase CML patients. Despite the remarkable initial clinic effects, it is now recognized that imatinib will unlikely cure patients because a small cell population containing leukemic stem cells (LSCs) with self-renewal capacity is insensitive to tyrosine kinase inhibitors.

In Chapter I, I briefly review the BCR-ABL kinase and its related signaling pathways. BCR-ABL kinase activates several signaling pathways including MAPK, STAT, and JNK/SAPK ...


Cooperating Events In Core Binding Factor Leukemia Development: A Dissertation, Dmitri Madera Mar 2011

Cooperating Events In Core Binding Factor Leukemia Development: A Dissertation, Dmitri Madera

GSBS Dissertations and Theses

Leukemia is a hematopoietic cancer that is characterized by the abnormal differentiation and proliferation of hematopoietic cells. It is ranked 7th by death rate among cancer types in USA, even though it is not one of the top 10 cancers by incidence (USCS, 2010). This indicates an urgent need for more effective treatment strategies. In order to design the new ways of prevention and treatment of leukemia, it is important to understand the molecular mechanisms involved in development of the disease.

In this study, we investigated mechanisms involved in the development of acute myeloid leukemia (AML) that is associated ...


Novel Therapeutic Targets For Ph+ Chromosome Leukemia And Its Leukemia Stem Cells: A Dissertation, Cong Peng May 2010

Novel Therapeutic Targets For Ph+ Chromosome Leukemia And Its Leukemia Stem Cells: A Dissertation, Cong Peng

GSBS Dissertations and Theses

The human Philadelphia chromosome (Ph) arises from a translocation between chromosomes 9 and 22 [t(9;22)(q34;q11)]. The resulting chimeric BCR-ABLoncogene encodes a constitutively activated, oncogenic tyrosine kinase that induces chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL). The BCR-ABL tyrosine kinase inhibitor (TKI), imatinib mesylate, induces a complete hematologic and cytogenetic response in the majority of CML patients, but is unable to completely eradicate BCR-ABL–expressing leukemic cells, suggesting that leukemia stem cells are not eliminated. Over time, patients frequently become drug resistant and develop progressive disease despite continued treatment. Two major reasons cause ...


Plagl2 Cooperates In Leukemia Development By Upregulating Mpl Expression: A Dissertation, Sean F. Landrette Jun 2006

Plagl2 Cooperates In Leukemia Development By Upregulating Mpl Expression: A Dissertation, Sean F. Landrette

GSBS Dissertations and Theses

Chromosomal alterations involving the RUNXI or CBFB genes are specifically and recurrently associated with human acute myeloid leukemia (AML). One such chromosomal alteration, a pericentric inversion of chromosome 16, is present in the majority of cases of the AML subtype M4Eo. This inversion joins CBFB with the smooth muscle myosin gene MYH11 creating the fusion CBFB-MYH11. Knock-in studies in the mouse have demonstrated that expression of the protein product of the Cbfb-MYH11fusion, Cbfβ-SMMHC, predisposes mice to AML and that chemical mutagenesis both accelerates and increases the penetrance of the disease (Castilla et al., 1999). However, the mechanism of transformation ...


Ube1l Is A Retinoid Target That Triggers Pml/Rarα Degradation And Apoptosis In Acute Promyelocytic Leukemia, Sutisak Kitareewan, Ian Pitha-Rowe, David Sekula, Christopher H. Lowrey, Michael J. Nemeth, Todd R. Golub, Sarah J. Freemantle, Ethan Dmitrovsky Mar 2002

Ube1l Is A Retinoid Target That Triggers Pml/Rarα Degradation And Apoptosis In Acute Promyelocytic Leukemia, Sutisak Kitareewan, Ian Pitha-Rowe, David Sekula, Christopher H. Lowrey, Michael J. Nemeth, Todd R. Golub, Sarah J. Freemantle, Ethan Dmitrovsky

Open Dartmouth: Faculty Open Access Scholarship

All-trans-retinoic acid (RA) treatment induces remissions in acute promyelocytic leukemia (APL) cases expressing the t(15;17) product, promyelocytic leukemia (PML)/RA receptor α (RARα). Microarray analyses previously revealed induction of UBE1L (ubiquitin-activating enzyme E1-like) after RA treatment of NB4 APL cells. We report here that this occurs within 3 h in RA-sensitive but not RA-resistant APL cells, implicating UBE1L as a direct retinoid target. A 1.3-kb fragment of the UBE1L promoter was capable of mediating transcriptional response to RA in a retinoid receptor-selective manner. PML/RARα, a repressor of RA target genes, abolished this UBE1L promoter ...