Research We Fund

Elucidating the role of FAM72A in EBV-driven B cell lymphomagenesis

This work focuses on characterizing the role of FAM72A in EBV-driven B cell tumorigenesis. This protein is upregulated by EBV during the transformation of B cells and overexpressed in many hematologic cancers. Using a combination of in vitro and in vivo EBV transformation models, high-throughput drug screens, and structural analysis we aim to find small molecules inhibitors that target FAM72A and determine if these drugs can prevent or hinder EBV-associated B cell malignancies.

Characterization and Targeting of Tumor-Associated Monocytes/ Macrophages that Limit the Efficacy of PD-1 Blockade in Lymphoma

Inhibition of the PD-1 exhaustion pathway enables the immune system to attack cancers. PD-1 blockade is now a standard treatment for relapsed classic Hodgkin Lymphoma (cHL) and a component of experimental frontline therapy. In patients with cHL, a newly identified population of monocytes/macrophages limits the efficacy of PD-1 blockade. We will characterize and target these tumor-programmed monocytes/macrophages for therapeutic benefit in patients with cHL and other lymphoid malignancies.

Bone Marrow Stromal Cell Senescence Induced by Dnmt3a-Mutant Hematopoiesis Drives Clonal Hematopoiesis and Transformation to Myeloid Malignancy

This project focuses on how age-associated clonal hematopoiesis (CH) alters the bone marrow (BM) microenvironment, and whether this promotes transformation of CH to acute myeloid leukemia (AML). I will utilize single cell RNA-seq data, genetic knockout models, and targeted inhibitors to perturb the non-hematopoietic and hematopoietic compartments of a mouse model of CH. The goal is to determine if manipulation of the BM microenvironment can attenuate CH and prevent AML transformation.

Identifying novel regulators of leukemic progression in GATA2-deficiency syndrome

GATA2 deficiency is an inherited pediatric syndrome with a high rate of progression to myeloid malignancy, the mechanisms of which remain largely undefined. Here, we will use our recently generated mouse model, Gata2R396Q, to determine the effects of GATA2 deficiency on hematopoietic function and identify novel drivers of myeloid malignancy via focused CRISPR screens. Our work will provide further insight into the mechanisms driving leukemic progression of this syndrome.

An integrated liquid biopsy framework for surveillance of residual disease and host immune status of T-cell lymphomas

I aim to develop an accurate disease monitoring system and identify immunologic determinants of development and progression in T-cell lymphoma (TCL). I will integrate noninvasive liquid biopsy methods by high-throughput sequencing. I will study blood samples at various milestones, including pre-diagnostic, diagnostic/baseline, and post-treatment specimens during the natural history of TCL. Using these novel tools and unique specimens, my goal is the development of effective therapies for TCL.

Deciphering the role of p53 signaling in NPM1-mutant AML

NPM1c and TP53 mutations are exclusive in acute myeloid leukemia (AML) despite both being commonly present in patients, suggesting a fitness disadvantage for cells with co-occurring mutations. However, the mechanisms underlying this exclusivity have not been explored. This project will utilize novel models to dissect the importance of TP53 signaling in NPM1c+ (pre)-leukemic stem cells. Generated results may highlight therapeutic opportunities for improved risk management of NPM1c+ AML patients.

Investigating the role of preleukemia duration and clonal burden in progression to AML

The development of acute myeloid leukemia (AML) is preceded by a “preleukemic” phase in which mutated hematopoietic stem cells expand due to a fitness advantage. Our work uses prospective models and analysis of patient samples to study how the duration of preleukemia and how the preleukemic clonal burden affect progression to AML. Results of our studies will shed new light on AML pathogenesis and help guide clinical management of preleukemic conditions such as clonal hematopoiesis.

Epigenetic Mechanisms in Acute Myeloid Leukemia

The goal of this project is to investigate the role of the epigenetic regulator Eleven-Nineteen-Leukemia (ENL) and its cancer mutations in acute myeloid leukemia (AML). Our studies leverage the expertise in chromatin biology, functional genomics, and AML modeling, as well as unique chemical compounds and mouse models. Results from this project will provide novel biological insights into our understanding of AML pathogenesis and facilitate the development of novel epigenetic therapies.

Modeling and targeting leukemic transformation of human hematopoietic stem cells

Our research seeks to understand how ordered acquisition of oncogenic mutations transforms human hematopoietic stem cells into myeloid malignancies. We leverage patient-derived induced pluripotent stem cells and primary normal and malignant stem cells to study how mutation cooperation drives leukemic progression in vitro and in vivo. Our long-term goal is to identify disease mechanisms and develop targeted therapies to eradicate malignant stem cells.

Improving CAR T-cell Therapy Efficacy in Acute Lymphoblastic Leukemia by Optimizing Design and Placement

Pediatric acute lymphoblastic leukemia (ALL) that is resistant to standard therapy is a challenge that has been partially overcome by T-cell therapy, yet relapse still occurs in up to 50%. We are conducting two clinical trials that test a next-generation T-cell therapy and the first incorporation of T-cell therapy into initial therapy. These trials will inform future development and the optimal place for this therapy with the goal of improving cure rates for children with very high risk ALL.

Clinical and molecular determinants of CLL eradication with targeted combination therapy

The genomic architecture of residual CLL and molecular determinants of disease progression after targeted combination therapy are unknown. In a phase 2 study of zanubrutinib and venetoclax in CLL, I will investigate the depth of response and genomic changes using cellular and circulating tumor DNA. Data generated from this proposal will provide foundational evidence to develop genomic markers for non-invasive monitoring of treatment response and precise prediction of outcome.

Inflammation-responsive mechanisms of malignant stem cell generation and eradication in multiple myeloma

The focus of my research is to elucidate the core molecular regulators of malignant stem cell generation in multiple myeloma. My approach addresses the tumor cell-intrinsic versus niche-dependent mechanisms of myeloma regeneration by exploring transcription factor expression and stemness profiles within single cells from primary samples and patient-derived models. The central goal of my research is to uncover novel therapeutic strategies and translate these into new myeloma treatments.

A Phase I/II Study of the Combination of ALX148, Rituximab and Lenalidomide in Patients with Indolent and Aggressive B-cell Non-Hodgkin Lymphoma

SIRPα+ macrophages mediate resistance to lenalidomide in B-cell lymphoma, limiting the activity of immunotherapy for these patients. Therefore, we propose a phase I/II study, investigating the safety and efficacy of ALX148, a novel fusion protein of the SIRPα binding domain, in combination with rituximab and lenalidomide in patients with B-cell lymphoma. We hypothesize that this combination will be safe and effective, providing a chemotherapy-free option for these patients.

Therapeutic exploitation of novel mouse models and metabolic interventions in leukemia

Our research program aims to gain a deeper understanding of the pathobiology of T-ALL and HSTL.

To this end, we will use novel mouse models, cutting-edge techniques and comprehensive genetic, pharmacological and metabolic interventions. In addition, we will perform unbiased experiments to identify novel therapeutic targets.

Our goal is to uncover new tools and targets for the treatment of T-ALL and HSTL, which could be used for the benefit of patients in the short/mid-term.

Analysis and therapeutic targeting of the immune regulatory and ubiquitination pathways in Anaplastic Large Cell Lymphoma and Hodgkin Lymphoma

My lab is focused on the immune regulatory mechanisms and ubiquitin-dependent machinery in lymphoma. We have established multiple high-throughput screening technologies and animal models to rapidly and accurately identify critical pathways that are suitable for targeted therapy and immunotherapy. Gaining insight into the pathological roles of these pathways can lead to improved understandings of the molecular circuitry that drives lymphoma pathogenesis and provide novel therapeutic strategies.

Genetic pathways of myeloid transformation and treatment response

Our central goal is to improve clinical outcomes in patients with myeloid malignancies through developing an enhanced mechanistic understanding of disease. We use multiomic analyses of primary patient samples combined with complementary laboratory models using mice and cell lines to generate and test our hypotheses. The results of our studies will help improve patient outcomes by identifying strategies to mitigate risk of disease progression/relapse and treatment toxicity.

Understanding the clonal origin, evolution, and progression of myeloid malignancies

The overarching focus of my research is to understand the clonal origin, evolution, and progression of myeloid malignancies and biological and clinical factors that influence the process. We tackle this question by analyzing patient samples with integrated approach combining single-cell omics, evolutionary genetics, and computational analytics. The ultimate goal of our research is to develop clinical strategies for early detection, prevention, and treatments of myeloid malignancies.

Stratified treatment of newly diagnosed MCL based on the presence or absence of high risk features utilizing non-cytotoxic agents.

We believe that regimens without chemotherapy can induce significant and durable remissions in patients with Mantle cell lymphoma (MCL). We will confirm this hypothesis by conducting two clinical trials stratified by the presence or absence of high risk features. We will utilize BH3 profiling and MRD testing to assist with predicting treatment response and remission. Our goal is to verify the efficacy of our regimen and prove the utility of BH3 profiling and MRD testing in outcome prediction.

Improving Bispecific CD20/CD19 CAR T-cell Therapy to Overcome Resistance Mechanisms in B-cell Malignancies

The objective of this proposal is to improve bispecific anti-CD20/anti-CD19 CAR T-cell activity and persistence by understanding impact of cell manufacturing parameters on final engineered CAR-T product and determining resistance mechanisms in relapsing patients. We will analyze patient apheresis, final CAR-T product, and peripheral blood samples from subjects enrolled on an ongoing clinical trial (NCT04186520). Data from these studies will advance CAR T-cell therapies for lymphoma patients.

Early Detection and Intervention in Smoldering Multiple Myeloma: population-based screening and treatment; Edit-SMM

We build on the success from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study, where over 80,000 consented to a nationwide screening for MM precursors. A unique cohort of patients with SMM diagnosed in iStopMM will be followed by clinical evaluation, linking to central health data registries, using novel biomarkers, and in-depth genetics. With precision early treatment we aim to induce a paradigm shift leading to improved quality of life and potentially a cure for MM.

Defining the Biologic and Therapeutic Significance of the Novel Long Noncoding RNA MYND in Multiple Myeloma

Long non-protein coding RNAs (lncRNAs) are fundamental for proper cell function, but their purpose is poorly understood in multiple myeloma. To systematically identify myeloma-promoting lncRNAs, we integrated gene expression profiling of myeloma patients with high-throughput loss-of-function studies in cell lines. Moreover, we optimized strategies to antagonize myeloma-promoting lncRNAs, thus paving the way to developing lncRNA inhibitors as the next generation of therapy.

Mechanisms of Pathogenesis by MYB Fusions in Blastic Plasmacytoid Dendritic Cell Neoplasm

The transcription factor MYB has long been associated with leukemia, but how it contributes to disease is poorly understood. Fusions of MYB to other proteins, causing MYB activation, are found in patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), but rare in other leukemias. I am using recently developed techniques to gain insight into how MYB fusions cause BPDCN. This will enable both new treatments for BPDCN and better understanding of the role of MYB in other leukemias.

Investigating the Role of ASXL1 Mutations in CALR-mutated Myeloproliferative Neoplasms

My research focuses on myeloproliferative neoplasms (MPN) and the mutations that drive the progression of these blood cancers. Currently, I am investigating mutations in the gene ASXL1, which are associated with a poor prognosis. I am using mouse models and patient-derived cells to determine how ASXL1 mutations mediate epigenetic changes in MPN. My goal is to identify ways of targeting the pathological mechanisms caused by ASXL1 mutation, resulting in new treatment strategies for patients.

SHP2 and BCL2 Inhibition in Acute Myeloid Leukemia

The goal of our work is to use a “bench to bedside and back” approach to develop new treatments for patients with relapsed/refractory AML. Through genetic analysis of patients who relapse or do not respond to standard and investigational treatments, we discover potential resistance mechanisms. In the lab, we test novel drugs and identify new drug targets that may address these resistance mechanisms when used in combination with other therapies. The overall goal of our research program is to improve treatment options and survival of patients with refractory AML.

Validation of Critical 1q21 Vulnerabilities in multiple myeloma

In previous studies of recurrently amplified 1q21 genes in myeloma, we identified ILF2 as a modulator of the DNA repair pathway, which promotes adaptive responses to genotoxic stress. Thus, ILF2 may have clinical utility as a biomarker of aggressive myeloma and blocking the ILF2-mediated repair signaling may enhance the effectiveness of current DNA-damaging agent-based therapies. We are seeking to determine the feasibility of therapeutically targeting ILF2 with antisense nucleotides and identify DNA repair effectors whose loss of function induces synthetic lethality in ILF2-depleted myeloma.

Dissecting the heterogeneity of leukemic and pre-leukemic clonal expansion to identify genes associated with leukemia relapse and genesis

My research investigates the heterogeneity of leukemic and pre-leukemic clonal expansion to identify genes associated with leukemia relapse and genesis. Contrary to conventional studies analyzing cell mixtures, my research uniquely probes the specific cells underlying leukemia development. We expect to identify the key cellular and molecular events that drive leukemia onset and relapse. These findings will help improve diagnosis and can serve as new therapeutic targets for treating leukemia.

Neonatal origins of pediatric AML

Coming soon.

Improving hematopoietic stem cell transplantation by defining novel regulators of engraftment

Blood-forming stem cells are routinely transplanted into patients to treat blood cancers. We discovered that multiple members of the GASP (G-protein coupled receptor Associated Sorting Proteins) family inhibit the function of blood-forming stem cells during transplantation. Our goal is to determine exactly how GASP family members inhibit these critical cells in order to inform our efforts to improve the efficiency of blood stem cell transplantation.

Role of HLX in leukemia induction and maintenance

We and others have shown how HLX overexpression keeps blood cells more immature by blocking their differentiation and promoting their proliferation, a characteristic which is inherent to AML. However, whether there is a causative role of HLX in the induction of AML is still unclear. Hence, the aim of my study is to better understand, using genetically engineered mice models, retroviral models, and human AML patient samples, how HLX drives AML at molecular level. This study will uncover potential therapeutic strategies for AML treatment in future.

Synergistic targeting of metabolic and epigenetic vulnerabilities in leukemia stem cells

Our lab is focused on identifying unique features that distinguishes acute myeloid leukemia (AML) stem cells from normal blood-forming stem cells. The cells that make more AML cells than others are called AML stem cells, and these cells need to be eradicated to achieve deep therapeutic responses. We believe targeting metabolism may achieve this goal and found strategies to target AML stem cell metabolism without harming normal stem cells. We hope that our study will lead to improved therapies against AML targeting metabolism to achieve deep remission with little toxicity.

The role of truncating ASXL1 mutations in disease initiation and progression of human myeloid malignancies

N/A

Targeting kinase-dependent dysregulation of transcription factor control in acute myeloid leukemia

Defining mechanisms of dysregulated gene control are central to understanding cancer and the development of effective therapies. Our research is focused on the mechanisms of gene control dysregulation in acute myeloid leukemia (AML), a refractory form of blood cancer that affects both children and adults. Using new methods for manipulating proteins, we are defining essential mechanisms by which AML cells enable cancer-causing gene expression. This work also allowed us to develop new drugs to specifically block this in cancer, but not healthy cells. Ongoing work aims to define precise mechanisms of cancerous gene control and develop definitive treatments for its control.

Dissecting the role of a key epigenetic modulator in Mixed Lineage Leukemia

We study how a protein called Dpy30 controls blood cancers by regulating chromatin, the physical structure where our genes reside. We study how this protein controls addition of a specific chemical group onto chromatin, thereby regulating expression of genes for leukemia in cells and animals. We are also developing chemicals to inhibit Dpy30’s activity in leukemia. We hope to better understand the role of Dpy30 in leukemia and identify Dyp30-inhibiting chemicals for leukemia treatment.

The role of FOXM1 downregulation in the development of clonal dominance in del(5q) MDS

Our research focuses on identifying the molecular mechanism underlying the development of a dominant population of abnormal stem cells in myelodysplastic syndrome (MDS) patients. We will employ mouse genetic models and MDS patient samples to elucidate the role of FOXM1 in the development of a dominant population of abnormal stem cells in vivo. This research program may lead to the identification of new effective therapeutic strategies for the treatment of early stages of MDS patients.

The role of Plek2 in the pathogenesis of myeloproliferative neoplasms

Our research focuses on the study of a novel therapeutic target, named Plek2, in the development of myeloproliferative neoplasms (MPNs). MPNs can progress to leukemia and there are currently no cures. We use animal models and patient samples to study how elevated levels of Plek2 causes the disease and identify approaches to suppress the function of Plek2. Our goal is to use the knowledge from this study to develop novel therapies to treat MPNs.

Improving BTK Inhibitor Therapy in Chronic Lymphocytic Leukemia Through Rational Combination Strategies

Ibrutinib is a targeted oral treatment for CLL that is safe and highly effective, however it must be given indefinitely which leads to chronic side effects and allows resistance to develop. We are conducting two clinical trials that add a second drug to ibrutinib to eliminate the remaining leukemia or ibrutinib-resistant leukemia cells. If these trials are successful, people taking CLL with or without resistance may be able to stop treatment in remission after taking an ibrutinib combination.

Cytokine induced memory-like NK cell immunotherapy to target post transplant relapse

Coming soon.

Novel combination strategies to enhance brentuximab vedotin efficacy in relapsed/refractory Hodgkin Lymphoma

New, non-chemotherapy treatments that use a patient’s own immune system have transformed the treatment of Hodgkin lymphoma (cHL). Typically used in patients with cHL that is resistant to standard treatment, these immune therapies can control the disease for months to years. However, in the long run, most patients will not be cured and will have immunotherapy-resistant cHL. My research evaluates strategies for reversing resistance to brentuximab vedotin (BV) immunotherapy for cHL by combining BV with other treatments in clinical trials.

Role of ERK isoforms in normal hematopoiesis and leukemia

Current therapies for cancers driven by “RAS/ERK’ pathway mutations, such as juvenile myelomonocytic leukemia (JMML), are either high risk (bone marrow transplant) or ineffective (targeted inhibitors). We have identified a unique dependency of JMML cell growth for a group of ERK targets, which are not required for normal blood cell growth. We are investigating this further and aim to identify the ERK targets responsible, which may provide new drug targets to treat JMML and other cancers.

Epigenetic Deregulation of Hematopoietic Cells with Aging and Disease

Our lab is focused on understanding how age-related epigenetic deregulation contributes to driving the functional decline of the hematopoietic system we see as we age. We are using genome-wide sequencing approaches to understand the changes in human hematopoietic stem and progenitor cells (HSPC) with aging at epigenomic level, along with in vitro and in vivo modeling of key changes that we hypothesize are the responsible drivers of the aging decline phenotype. Our overarching goal is to identify key drivers of functional HSPC decline to ultimately develop methods for modulating these drivers and achieve HSC rejuvenation.

Targeting the interaction of leukemia stem cells with their niche to treat myelofibrosis

Bone marrow scar formation (fibrosis) is a hallmark of myelofibrosis and contributes significantly to the disease progression. We use mouse genetics to model myelofibrosis and understand the cellular and molecular makeup of the diseased microenvironment. We aim to understand the composition and alteration of the bone marrow microenvironment in myelofibrosis. This may provide novel therapeutic targets for myelofibrosis.

Overcoming ibrutinib resistance in mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive blood cancer which affects about 3,000 individuals in the United States annually. Despite advances of novel therapies in blood cancers, MCL remains incurable, and patients ultimately succumb to disease. We seek to evaluate longitudinal samples from patients with MCL treated with novel therapies to understand the mechanisms of drug resistance. We identify novel targets, with a particular focus on protein turnover pathways, to overcome drug resistance and improve survival of patients with MCL.

All-in-one for myeloma: a single therapy to combine CAR T cells and bispecific antibodies to engage both innate and adaptive immune responses

This project is designed to develop a novel cell therapy to treat relapse/refractory multiple myeloma (MM), an incurable cancer. We target BCMA, a protein highly expressed on MM compared to normal cells, with CAR T cells that also secrete a bispecific antibody that can engage all cytolytic cells, including various endogenous T cells, natural killer (NK) cells, and NKT cells to kill MM cells. We aim to complete all preclinical studies so that the therapy is ready for future clinical studies.

Synergism of cell-intrinsic and cell-extrinsic factors in the clonal evolution of pre-malignant HSCs

We study the mechanisms of clonal hematopoiesis (CH), a process by which mutations provide hematopoietic stem cells (HSCs) with a fitness advantage. CH can precede the development of blood cancer. We use cutting-edge techniques to understand the effects of these mutations on HSC behavior. Our long-term goal is to identify ways to inhibit the growth of these mutant HSCs while sparing normal HSCs in people with CH. This may someday provide a blood cancer prevention method by eliminating the cells which carry the initial cancer-driving mutations.

Investigating the Role of Adenylate Kinase 2 in Multiple Myeloma

The goal of my research is to characterize the role of the cellular metabolic regulator AK2 in multiple myeloma (MM) pathogenesis and therapy resistance. A series of molecular, biochemical, and functional assays will be performed using laboratory models to define the basis of MM cell dependence on AK2 and elucidate its role in MM progression and drug resistance. This work will highlight novel metabolic vulnerabilities in MM that can be targeted to further enhance therapeutic outcomes.

Pharmacological inhibition of the transcription factor PU.1 as a novel treatment for acute myeloid leukemia

Transcription factors are components of a cell which control our genetic information and are known to have altered function in diseases such as Acute Myeloid Leukemia (AML). I am investigating how we can better understand and use novel transcription factor drugs as therapy for AML. This involves using CLICK-chemistry drug localization studies and creating transcription factor occupancy maps of the genome. Overall, my work will help to understand the inner workings of transcription factors in disease and provide a new therapeutic option for the treatment of AML.

EBV promotes Burkitt's lymphoma progression through microprocessor sequestration.

This proposal aims to understand the molecular mechanisms underlying response to AZA therapy in MDS, as a basis for developing more effective therapies. A ribonucleotide, AZA’s effects on RNA remain unknown. Here, we will investigate the impact of in vivo AZA therapy on RNA alternative splicing and DNA demethylation in MDS patients. Secondly, we will investigate whether AZA treatment exposes neoepitopes in the dysplastic cells of patients, which could be exploited for cancer immunotherapy in MDS

Targeting non-genetic mechanisms of therapeutic resistance in Acute Myeloid Leukaemia

Drug resistance in AML can develop via a non-genetic process which remains poorly understood. Using our novel cellular barcoding technology that can trace the growth of thousands of cancer cells, our research will identify genes that are switched on or off in AML cells that lead to drug resistance and relapse. This work will reveal the factors underpinning non-genetic drug resistance that may be targeted with new drugs to prevent relapse and ultimately improve quality of life and survival.

Decipher and Target AML Cell Dependency on Epigenetic Mutations

The goal of our program aims to understanding the general roles of DNA methylation machineries in epigenetic regulation and cancerous transformation seen in hematological cancers. Routinely, we take a set of integrated biochemical, genomics, oncology, and medicinal chemistry approaches to tackle the broad and critical questions in this field. Our findings shall not only promote current understanding of how hematological malignancies occur but also help develop novel therapeutic approaches.

Functional and mechanistic roles of BCAA metabolism in the progression of myeloproliferative neoplasms

The processes that control the progression of myeloproliferative neoplasms to leukemic transformation remain largely unknown. We have developed genetic mouse models that recapitulate leukemia progression in humans. We aim to discover new regulators and pathways controlling the propagation of leukemia stem cells as targetable vulnerabilities. Our study promises to provide critical insights into developing new and generalizable therapies to selectively eliminate leukemia stem cells.