Blood Cancers

Current Projects
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
Ann Mullally, MD

Myeloproliferative neoplasms (MPN) are a type of blood cancer sometimes considered to be "pre-leukemias" which can progress to leukemia and are also lethal cancers in their own right. A population of rare hematopoietic stem cells (HSC), called MPN disease-propagating cells, typically harbor mutations that cause the cells to overproliferate. These mutated HSC produce abnormal cancerous blood cells that over time can eliminate the normal blood cells in the bone marrow. In MPN, the cancerous blood cells secrete an excess of substances called growth factors that allow cancer cells to survive.

Dr. Mullally aims to understand which of the growth factors help the mutated HSC to survive and to then use drugs to block the activity of these growth factors, thus killing the mutated HSC. This approach will lead to more successful treatments for MPN and leukemia, resulting in a higher cure rate for patients. 

Project title: "Determining the role of aberrant growth factor signaling in maintaining disease-propagating cells and mediating JAK2 inhibitor resistance in myeloproliferative neoplasms"
Institution: Brigham and Women's Hospital
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Benjamin L. Ebert, MD, PhD, and Jerome Ritz, MD
Cancer Type: Blood
Research Area: Stem Cell Biology
Sigrid Nachtergaele, PhD

Dr. Nachtergaele [HHMI Fellow] is investigating the roles of a chemical modification of mRNA called methylation. Many enzymes that add and remove RNA modifications impact developmental processes and cancer proliferation, but how they are regulated remains a mystery. She aims to identify the mechanisms by which mRNA methylation alters gene expression and eventually results in altered cell signaling and growth. Her goals are to understand these regulatory principles, to uncover how they become misregulated in disease, and to exploit these processes to identify novel cancer therapeutic targets.

Project title: "The dynamic N1-methyladenosine methylome in eukaryotic mRNA"
Institution: The University of Chicago
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Chuan He, PhD
Cancer Type: Blood, Breast, Lung
Research Area: Chemical Biology
Stephen T. Oh, MD, PhD

Myeloproliferative neoplasms (MPNs) are a group of blood cancers in which a malignant cell population proliferates out of control. Myelofibrosis (MF) is one type of MPN in which the bone marrow becomes replaced by scar tissue, leading to progressive failure of normal blood cell functions and ultimately death, on average five years after initial diagnosis. MPNs, including MF, can evolve to secondary acute myeloid leukemia (sAML), which is almost invariably fatal. There is no reliable curative treatment currently available for MPNs or MF. Targeted inhibitors of a protein called JAK2 provide significant symptomatic benefit for MF patients. However, these treatments do not cure the disease, nor has it been shown that they can prevent or delay progression to sAML. Dr. Oh [Doris Duke-Damon Runyon Clinical Investigator] aims to investigate the cellular abnormalities that underlie these blood cancers. These studies have the potential to lead to the development of improved treatments for MPNs.

Project title: "Leveraging NFkB pathway dysregulation for therapeutic benefit in myeloproliferative neoplasms"
Institution: Washington University
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Daniel C. Link, MD
Cancer Type: Blood
Research Area: Signal Transduction
Sarah Naomi Olsen, PhD

Dr. Olsen is investigating new therapeutic options to treat acute myeloid leukemia (AML), an aggressive form of childhood cancer. One subtype of AML is characterized by a chromosomal translocation involving the MLL (KMT2A) and the AF9 gene, resulting in an abnormal MLL-AF9 fusion protein. Dr. Olsen is targeting the MLL-AF9 fusion protein using a newly developed protein degradation approach. Characterizing the consequences of direct MLL-AF9 degradation will provide important mechanistic insight into how this mutant protein modulates leukemia and help guide the development of combination therapeutic approaches for long-term responses in pediatric AML patients.

Project title: Targeted degradation of the MLL-AF9 fusion oncoprotein in acute myeloid leukemia
Institution: Dana-Farber Cancer Institute
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Scott A. Armstrong, MD, PhD
Cancer Type: Blood, Pediatric
Research Area: Epigenetics
Hanjing Peng, PhD

Dr. Peng seeks to identify compounds that inhibit the proteasome, the protein degradation machinery in the cell that maintains the balance of cell growth and death. Inhibitors that regulate proteasome function are potential anticancer drugs. Inspired by the functional mechanism of a class of natural products that includes FK506 and rapamycin, she has designed and constructed a synthetic library of compounds (macrocyclic "rapafucin") in search of potent proteasome inhibitors. She hopes to discover new anticancer drug candidates with lower toxicity or side effects than current drugs. 

Project title: "Targeting the proteasome using a hybrid, combinatorial rapafucin library"
Institution: The Johns Hopkins University
Award Program: Fellow
Sponsor(s) / Mentor(s): Jun O. Liu, PhD
Cancer Type: Blood
Research Area: Drug Discovery
Maxim Pimkin, MD, PhD

Dr. Pimkin is identifying and characterizing the most critical transcription factors (proteins that regulate the function of genes), called core regulatory circuitries (CRCs), in various types of AML. This will provide new insights into the most critical mechanisms of AML survival and identify new targets for drug development. Preliminary data show that CRCs can accurately and reliably predict critical genes necessary for AML cancer cell survival, suggesting a practical way of identifying potential therapeutic targets. Dr. Pimkin hopes to create a unified understanding of the common and different ways in which AML subtypes arise, as well as create an unprecedented way of predicting common and subtype-specific AML vulnerabilities. 

Project title: Divergent core transcriptional circuitries highlight context-specific vulnerabilities in AML
Institution: Harvard Medical School
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Stuart Orkin, MD
Cancer Type: Blood, Pediatric
Research Area: Genomics
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