Blood Cancers

Current Projects
Andrew J. Dunbar, MD

Mutations in the cancer-causing oncogene JAK2 are a hallmark of myeloproliferative neoplasms (MPNs), a blood disorder characterized by over-production of mature blood cells. While currently available JAK2 inhibitors improve symptoms, they are unsuccessful at completely eradicating diseased cells, so remissions are rare. Using genetically engineered mice, Dr. Dunbar will investigate how MPN cells remain dependent on JAK2 signaling for cell growth, and how additional mutations in the epigenome (the proteins involved in regulating gene expression) might contribute to drug resistance. His research aims to identify improved JAK2 inhibitors and lend insight into whether targeting both oncogenic drivers and epigenetic defects could be required for effective therapy. Ultimately, he hopes these findings will translate into better treatments for patients with these cancers.

Project title: "Interrogating functional contribution of JAK2V617F in the maintenance of myeloproliferative neoplasms"
Institution: Memorial Sloan Kettering Cancer Center
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Ross L. Levine, MD
Cancer Type: Blood
Research Area: Cancer Genetics
Christopher J. Gibson, MD

Christopher’s research centers on the earliest steps whereby normal cells transform into abnormal cells with the potential to become cancer. He will focus on better understanding the first steps of the process by which normal blood cells become lymphomas, cancers that are generally thought to arise from blood cells that have already committed to becoming lymphocytes, an important component of the immune system. He hypothesizes, however, that some lymphomas actually arise from earlier hematopoietic stem cells (HSCs). He will interrogate this hypothesis by studying a cohort of lymphoma patients who also have detectable genetic mutations in HSCs that are known to be associated with blood cancers – a condition known as clonal hematopoiesis of indeterminate potential, or CHIP – to determine whether the mutations in the HSCs were the earliest events in the development of the patients’ lymphomas. Having a better understanding of lymphomas’ cellular basis will hopefully allow new insights into their clinical behavior and therapeutic vulnerabilities.

Project title: "Elucidating the connection between clonal hematopoiesis and lymphoma in humans"
Institution: Dana-Farber Cancer Institute
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Benjamin L. Ebert, MD, PhD
Cancer Type: Blood, Other Cancer
Research Area: Cancer Genetics
Alejandro Gutierrez, MD

It remains unclear why some patients' tumors can be cured with chemotherapy, whereas other tumors that appear to be nearly identical are completely chemoresistant. Dr. Gutierrez focuses on this issue in a particularly high-risk subset of T-cell acute lymphoblastic leukemia, a disease that most commonly affects older children and young adults. His goals are to define the molecular basis of resistance to conventional chemotherapy in patients with this disease, and to leverage this knowledge to develop a therapeutic strategy to restore chemosensitivity. Ultimately, this could lead to significant improvements in clinical outcome for these patients.

 

Project title: "Mechanisms and therapeutic targeting of EZH2-dependent chemoresistance in T-ALL"
Institution: Boston Children's Hospital
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Stuart Orkin, MD and Anthony Letai, MD, PhD
Cancer Type: Blood
Research Area: Chemoresistance
Andrew M. Intlekofer, MD, PhD

New drugs that target metabolic pathways have shown promise for the treatment of cancer, but the benefits of these drugs have been restricted to rare patients whose cancers have mutations in specific metabolic enzymes. Dr. Intlekofer identified a metabolic pathway whereby subpopulations of genetically identical cancer cells produce a metabolite called L-2-hydroxyglutarate (L-2HG) that induces stem cell-like properties associated with resistance to anti-cancer therapies. He is investigating the mechanisms by which L-2HG regulates the identity and function of cancer stem cells in order to determine whether targeting the L-2HG pathway represents a broadly applicable strategy for treating cancer.

Project title: "Metabolic coupling of the hypoxic niche to stemness"
Institution: Memorial Sloan Kettering Cancer Center
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Ross L. Levine, MD
Cancer Type: Blood, All Cancers
Research Area: Stem Cell Biology
Elise C. Jeffery, PhD

Dr. Jeffery studies “stromal cells” that support the function of blood stem cells in the bone marrow. Cancer treatments such as irradiation and chemotherapy damage the bone marrow, and the repair of this tissue is crucial for the recovery of the blood system. She is characterizing the role of a newly identified factor produced by stromal cells in this rebuilding process. These studies have the potential to enhance our understanding of bone marrow repair, and to identify new methods for improving the recovery of the blood system in cancer patients following irradiation or chemotherapy.

Project title: "Characterizing a new hematopoietic stem cell niche factor"
Institution: University of Texas Southwestern Medical Center
Award Program: Fellow
Sponsor(s) / Mentor(s): Sean Morrison, PhD
Cancer Type: Blood
Research Area: Stem Cell Biology
Michael A. Koldobskiy, MD, PhD

Dr. Koldobskiy studies the ways that cancer cells rely on “epigenetic” modifications, or chemical marks that modify the expression of genes without a change in the genetic sequence itself. Variability of epigenetic marks allows cancer cells flexibility in turning genes on and off, and may account for resistance to treatment. By dissecting the mechanisms of epigenetic modification in pediatric acute lymphoblastic leukemia (ALL), the most common cancer in children, he aims to identify new targets for treatment.

Project title: "DNA methylation stochasticity in pediatric pre-B cell acute lymphoblastic leukemia"
Institution: The Johns Hopkins University
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Andrew P. Feinberg, MD
Cancer Type: Blood, Pediatric
Research Area: Epigenetics
Kathrin Leppek, PhD

Dr. Leppek [Layton Family Fellow] aims to combine RNA and ribosome biology with developmental biology to investigate how cells regulate protein synthesis through a process called translation. This process requires regulatory mechanisms to fine-tune when and where genes are expressed. Defective expression of certain genes gives rise to uncontrolled growth and metastasis of cancer cells. She will identify and characterize molecular components that play a functional role in mediating translational control during embryogenesis. This will be invaluable for our understanding of how deregulation of accurate gene expression underlies human diseases such as cancer.

Project title: "Mechanistic characterization of 5’UTR RNA elements that confer translational specificity to shape vertebrate embryonic development"
Institution: Stanford University
Named Award: Layton Family Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Maria Barna, PhD
Cancer Type: Blood, Gastric, Gynecological, Breast, Colorectal, Lung, Pancreatic
Research Area: Developmental Biology
Loretta S. Li, MD

Approximately 10-15% of pediatric and adult patients with B-cell acute lymphoblastic leukemia (B-ALL) have a high-risk form of the disease characterized by rearrangements of a gene called CRLF2. Alterations of this gene result in increased expression of the CRLF2 protein and promote leukemia development. When treated with conventional chemotherapy, patients with CRLF2 gene alterations do poorly. Their leukemias are dependent on an enzyme called JAK2 for survival, yet no targeted therapies with proven efficacy are currently available. Dr. Li has unique access to a new drug called CHZ868, which turns off JAK2 enzyme activity, potently kills B-ALL cells, and improves overall survival in mice with JAK2-dependent B-ALL. Treatment with CHZ868 alone is not curative, however, and all mice eventually succumb to progressive leukemia. Using JAK2-dependent B-ALL cells and mouse models, she will study how leukemia becomes resistant to JAK2 inhibitors. Her goal is to identify combinations of agents that can prevent or overcome resistance to a single therapy and also guide the development of new JAK2 inhibitors for patients.

Project title: "Mechanisms of disease and resistance in CRLF2-rearranged B-cell acute lymphoblastic leukemia"
Institution: Dana-Farber Cancer Institute
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): David M. Weinstock, MD
Cancer Type: Blood, Pediatric
Research Area: Cancer Genetics
Christine Mayr, MD, PhD

[Island Outreach Foundation Innovator of the Damon Runyon-Rachleff Innovation Award]

Cancer is thought to arise through a series of genetic mutations in the DNA sequence. Depending on the location of these errors and the genes that are affected, these mutations lead to the many different features that characterize cancer cells such as uncontrolled proliferation, escape from cell death and metastasis.

Dr. Mayr proposes the existence of a new type of anomaly that can lead to cancer: non-genetic aberrations induced by modifications of RNAs, which have so far been excluded from large-scale cancer genomics efforts. She has developed a new method to identify this type of aberration in different cancers and will investigate its frequency and functional consequences for tumor growth. Her studies will help to broaden the understanding of cancers and may also help in the design of new therapeutics.

 

Project title: "A functional atlas of lymphoma specific aberrations generated by RNA processing"
Institution: Memorial Sloan Kettering Cancer Center
Named Award: Island Outreach Foundation Innovator
Award Program: Innovator
Cancer Type: Blood
Research Area: Cancer Genetics
Robert K. McGinty, MD, PhD

Dr. McGinty is using protein chemistry and structural biology to study epigenetic changes to the composition and structure of chromatin, the physical state of the DNA in each cell’s genome. These epigenetic modifications are chemical marks that modify the expression of genes without a change in the genetic sequence itself. Divergent patterns of gene expression lead to the development of diverse cell types and functions, and their inappropriate regulation is correlated with many human diseases, especially cancer.   

Project title: "Structural studies of the MLL1 Core Methyltransferase complex"
Institution: Pennsylvania State University
Award Program: Dale Frey Scientist
Cancer Type: Blood
Research Area: Chromatin Biology
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