Blood Cancers

Current Projects
Lucas Farnung, PhD

About 70% of pediatric leukemias and 10% of adult leukemias are caused by a genetic disruption in which the mixed lineage leukemia (MLL) 1 gene breaks off and attaches to a different chromosome. This event, known as a chromosomal translocation, gives rise to a distinct subset of leukemias called MLL-rearranged acute myeloid and lymphoblastic leukemias (AML or ALL). Novel treatments for these cancers represent a major unmet medical need. However, the development of therapeutics is hampered by a lack of basic understanding of how the MLL translocations disrupt the function of affected cancer cells. Dr. Farnung will use biophysical and structural biology approaches to visualize how MLL translocations function at the atomic level and influence the important process of gene transcription. His work will elucidate the precise molecular mechanisms that drive acute leukemias and provide a platform for the development of novel therapeutic strategies against these cancers.

Project title: "Understanding the mechanistic basis of gene expression regulation by MLL complexes in cancers"
Institution: Harvard Medical School
Award Program: Innovator
Cancer Type: Blood, Pediatric
Research Area: Structural Biology
Ryan A. Flynn, MD, PhD

Many cancer diagnostic and treatment strategies use markers on the cell surface to find and kill cancer cells in a sea of healthy tissue. Dr. Flynn's research aims to expand our knowledge of what molecules are found on the surface of cancer cells. He will focus on acute myeloid leukemia (AML), as there is a major unmet clinical need for new curative treatments. Specifically, he aims to define RNA as a new cell surface molecule that could have unique structures on AML cells. With this knowledge he will develop antibodies to selectively detect cancer cells and enable tumor killing. Because tumors from other parts the body also express RNA on their surface, this strategy is expected to be broadly applicable to other cancer types.

Project title: "Tools to target novel cell surface ligands in cancer"
Institution: Boston Children's Hospital
Award Program: Innovator
Cancer Type: Blood
Research Area: Chemical Biology
(Peter) Geon Kim, MD

Blood stem cells, which give rise to various blood cells in the body, acquire mutations with increasing frequency as we age. In the absence of blood cancer development, this state is called clonal hematopoiesis. Up to a quarter of individuals over 60 years old will have recurrent mutations detected in their blood. Recent studies suggest that those with clonal hematopoiesis have an increased risk of developing heart disease and blood cancer, as well as increased levels of inflammatory cytokines – signaling molecules released by immune cells to promote inflammation. Dr. Kim will dissect the mechanisms underlying increased inflammation, which could provide insight into various inflammatory conditions associated with clonal hematopoiesis and potentially elucidate how clonal hematopoiesis progresses into blood cancer.

Project title: "Elucidating the mechanisms of inflammation in clonal hematopoiesis"
Institution: Dana-Farber Cancer Institute
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Benjamin L. Ebert, MD, PhD
Cancer Type: Blood
Research Area: Cancer Genetics
Nora Kory, PhD

Cancer cells rely on efficient uptake, conversion, and exchange of nutrients and vitamins to support their rapid growth and survival. The molecular transport channels that allow passage of nutrients between the different cellular compartments are critical for the survival of cancer cells and are thus promising as potential drug targets. However, drug discovery efforts are hampered by a lack of basic understanding of these channels' identities, functions, and regulation inside cancer cells. Dr. Kory's research aims to identify transporters central to cancer cell nutrient supply and detoxification pathways and determine their role in the emergence, survival, and aggressiveness of cancer. Her research is relevant to all cancers, but particularly pediatric, blood, and breast cancers.

Project title: "Targeting mitochondrial transporters in cancer"
Institution: Harvard T.H. Chan School of Public Health
Award Program: Innovator
Cancer Type: Blood, Gynecological, All Cancers
Research Area: Biochemistry
Mark B. Leick, MD

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Intensive chemotherapy cures only a subset of patients, and immunotherapy has had limited success in AML. One novel approach is chimeric antigen receptor (CAR) T cell therapy, which involves genetically engineering a patient's own immune cells to target cancer cells. The difficulty with this approach is that the majority of available targets present on AML cells also reside on many normal cells. Based on emerging data demonstrating overexpression of the gene CD70 in AML cells compared to normal tissues, Dr. Leick [The Mark Foundation for Cancer Research Physician-Scientist] and his colleagues have recently optimized a CD70-targeted CAR T therapy and demonstrated its efficacy in AML. Despite the superiority of this CAR over prior versions, however, it is less effective against AML cells that present a low amount of the antigen. Dr. Leick is now working to improve this CAR through genetic modification and/or a dual targeting approach. His work has the potential to generate a safe, highly potent, optimized strategy for treating this leukemia.

Project title: "Engineering novel CAR T cells for AML: translating lessons from correlative studies and other diseases"
Institution: Massachusetts General Hospital
Named Award: The Mark Foundation for Cancer Research Physician-Scientist
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Marcela V. Maus, MD, PhD
Cancer Type: Blood
Research Area: Experimental Therapeutics
Julia Su Zhou Li, PhD

Dr. Li’s research aims to uncover a missing link between repeated DNA sequences, genomic instability, and viruses. While abnormal expansion of “repeats” has been found at unstable genomic regions, known as fragile sites, that are implicated in cancer growth, the mechanisms and consequences of this genomic instability remain poorly understood. Dr. Li recently discovered a cluster of Epstein Barr Virus (EBV)-like repeat sequences in the genome that breaks when bound by abnormally high levels of EBV antigens. These findings illustrate how a chromosome can be broken in long-term EBV infection, which can threaten genome stability and trigger cancer development. Dr. Li aims to leverage this discovery to advance our understanding of how broken repeats threaten genome integrity for clinical screening of individuals susceptible to EBV-associated diseases, and for the prevention and treatment of disease in these individuals. This research could also lead to the discovery of other virus-like repeats and the potential biological function of these virus-like repeats in our genome.  

Project title: “Uncovering the link between repetitive DNA, genomic instability, and tumor viruses”
Institution: University of California, San Diego
Award Program: Dale Frey Scientist
Cancer Type: Blood, Other Cancer, Sarcoma
Research Area: Chromatin Biology
(Kathy) Fange Liu, PhD

Sex differences are markedly evident in many types of cancer, and one of the major contributors to sex-biased differences lies in the sex chromosomes. In contrast to the traditional view that Y chromosome-encoded proteins only function in male reproductive organs, recent evidence suggests that select Y chromosome-encoded proteins are also expressed in male non-reproductive tissues. Furthermore, dysregulation of the Y chromosome-encoded proteins has been implicated in cancers in non-reproductive organs. Upon closer examination, this subgroup of Y chromosome proteins each has corresponding proteins on the X chromosome. Dr. Liu will study the function of the Y chromosome-encoded proteins and whether and how protein sequence differences from their X chromosome-encoded counterparts lead to functional distinctions in cancer development.

Project title: "Y chromosome proteins in sex bias of cancers in non-reproductive organs"
Institution: University of Pennsylvania
Award Program: Innovator
Cancer Type: Blood
Research Area: Biochemistry
Senén D. Mendoza, PhD

In addition to acute illness, viruses can cause cancers. While our understanding of cellular immunity against viruses that have DNA-based genomes is robust, we know less about how cells protect themselves against RNA-based viruses such as hepatitis C, a leading cause of liver cancer. Because many cellular defenses against viruses are known to be shared between mammals and bacteria, Dr. Mendoza [HHMI Fellow] is looking for new cellular defenses against RNA viruses in bacteria and will investigate how these defenses work. The resulting discovery of anti-viral defenses will broaden our understanding of how cells protect themselves against RNA viruses, which will improve our capacity to support patients' immune systems when infected with cancer-causing RNA viruses. Dr. Mendoza received their PhD from the University of California, San Francisco, and their BS from the University of Miami.

Project title: "Discovery and characterization of bacterial immunity against RNA phages"
Institution: Massachusetts Institute of Technology
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Michael T. Laub, PhD
Cancer Type: Blood, Gastric
Research Area: Virology
Xiaoli Mi, MD

Chimeric antigen receptor (CAR) T cells are a type of immunotherapy that uses genetically engineered T cells from patients to treat cancer. While a one-time treatment has the potential to generate long-term protection from relapse, CAR T cells often fail due to poor persistence. Dr. Mi recently studied samples from patients with durable remissions of leukemia and found that rare persistent CAR T cells share a distinct set of molecular and cellular features. She will now define the properties of persistent CAR T cells across multiple blood cancers, trace their T cell origins and evolutionary dynamics using novel technologies, and experimentally evaluate her findings in preclinical models. These studies could illuminate how CAR T cells change over time in patients and help guide development of future cellular therapies with more durable effects for patients with different types of cancers.

Project title: "Origin and evolution of long-lived CAR T cells in patients with hematologic malignancies"
Institution: Memorial Sloan Kettering Cancer Center
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Omar Abdel-Wahab, MD, and Dan A. Landau, MD, PhD
Cancer Type: Blood
Research Area: Genomics
Manuel Osorio Valeriano, PhD

Human cells compact their vast genomes into the small confines of the nucleus by wrapping their DNA into a highly complex structure called chromatin. Packaging DNA into chromatin, however, affects all nucleic acid-transacting machines (e.g., transcription factors) that need to access the genomic information stored in the DNA. NuRD is a large multi-subunit protein complex that plays a major role in making chromatin either accessible or inaccessible. Dysregulation of NuRD and aberrant targeting of the complex can result in the emergence of several types of cancers, including breast, liver, lung, blood, and prostate cancers. Dr. Osorio Valeriano’s [Philip O'Bryan Montgomery, Jr., MD, Fellow] work will reveal mechanistic aspects of NuRD-mediated chromatin regulation and pave the way for the development of novel therapeutic approaches that target cancers more effectively. Dr. Osorio Valeriano received his PhD from Philipps University and his MSc and BSc from the National Autonomous University of Mexico.

Project title: "Molecular and structural basis of gene expression regulation by the nucleosome remodeling and deacetylase (NuRD) complex in human cancer"
Institution: Harvard Medical School
Named Award: Philip O’Bryan Montgomery Jr. MD Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Lucas Farnung, PhD, and Danesh Moazed, PhD
Cancer Type: Blood, Gastric, Breast, Lung, Prostate
Research Area: Structural Biology
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