Blood Cancers

Current Projects
Sigrid Nachtergaele, PhD

Dr. Nachtergaele is investigating the roles of RNA methylation, a process that chemically tags mRNA to alter gene expression and protein production. She has discovered a novel enzyme (m1A) that modifies RNA in this way and aims to uncover how malfunctions in this process can lead to cancer. Her investigations will expand the understanding of how mRNA modifications are regulated and result in altered cell signaling and growth in normal and cancer cells.  Building on this knowledge, her goal is to identify novel therapeutic targets for cancer.

Project title: "The dynamic N1-methyladenosine methylome in eukaryotic mRNA"
Institution: The University of Chicago
Award Program: Dale Frey Scientist
Cancer Type: Blood, Breast, Lung
Research Area: Chemical Biology
Alexandra Nguyen, PhD

Dr. Nguyen aims to identify the molecular differences between cancer cells and healthy cells, using large-scale genetic approaches in acute myeloid leukemias. Cancer cells exhibit a high degree of diversity in the cellular pathways utilized for survival. Identifying these cellular differences could provide a method to strategically target and kill cancerous cells while minimizing the off-target effects to healthy cells.

Project title: "Defining the cell type specific cell division requirements in acute myeloid leukemias"
Institution: Whitehead Institute for Biomedical Research
Award Program: Fellow
Sponsor(s) / Mentor(s): Iain M. Cheeseman, PhD
Cancer Type: Blood, Other Cancer
Research Area: Cancer Genetics
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
Juhee Pae, PhD

Dr. Pae is investigating the regulation of immune B cell proliferation in Germinal Centers (GCs). While this process is critical for bodies to resist infection, it must be carefully regulated. On one hand, not having enough B cells can lead to immunodeficiency and susceptibility to infections. Conversely, inappropriate activation is a major driver of malignant transformation and cancers such as B cell lymphomas. Dr. Pae’s research has the potential to shed light on how lymphomas form and to aid in the rational design of cancer therapeutics.

Project title: "Mechanisms of germinal center B Cell proliferation"
Institution: The Rockefeller University
Award Program: Fellow
Sponsor(s) / Mentor(s): Gabriel D. Victora, PhD
Cancer Type: Blood, Other Cancer
Research Area: Basic Immunology
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
Cara A. Rabik, MD, PhD

Dr. Rabik is examining how mutations in the WT1 gene result in methylation changes in acute myeloid leukemia (AML). WT1 recruits the machinery necessary for demethylation to its target genes, ultimately regulating gene expression. When WT1 is mutated, these genes remain methylated and inactive, preventing normal hematopoiesis. She is identifying WT1 target genes and mapping their methylation landscape both in leukemic and normal settings. She will also test drugs designed to cause demethylation to evaluate if these drugs can treat the leukemia caused by mutations in WT1.

Project title: "Determination of the role of WT1 in hematopoiesis and leukemogenesis"
Institution: The Johns Hopkins University
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Patrick A. Brown, MD
Cancer Type: Blood, Pediatric
Research Area: Epigenetics
Marissa Rashkovan, PhD

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, accounting for 10-15% of pediatric and 25% of adult ALL cases. While survival rates have improved with intensified treatment regimens, 25% of pediatric T-ALL cases still relapse because of refractory disease. Furthermore, the intensity of these treatment regimens has led to increased secondary effects in these children later in life. This underscores the need for the development of efficient, targeted and highly specific anti-leukemic therapies to treat T-ALL. Dr. Rashkovan studies a distinct subgroup of immature T-ALL, ETP-ALL, which phenotypically resembles early thymic progenitors (ETPs), has been associated with early relapse, and poor prognosis. There is a particularly urgent need for targeted therapies for ETP-ALL, which is notoriously difficult to treat. She will assess the metabolic vulnerabilities of ETP-ALL in order to propose new, targeted therapies which could be beneficial for the treatment of this high-risk leukemia group.

Project title: "Targeting metabolic vulnerabilities in ETP-ALL"
Institution: Columbia-Presbyterian Medical Center
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Adolfo A. Ferrando, MD, PhD
Cancer Type: Blood, Pediatric
Research Area: Cancer Genetics
Jose Reyes, PhD

Dr. Reyes focuses on Complex-Karyotype Acute Myeloid Leukemia (CK-AML), an aggressive form of AML with poor prognosis and limited treatment options. Dr. Reyes is using mouse models and single-cell technologies to follow the parallel evolution of cancer cells from the time of disease onset until its terminal stage. This approach may forecast the evolution of heterogeneous cancer cell populations with the goal of identifying targets that are involved with a cancer cell's ability to adapt to and recur after treatment.

Project title: "Dynamics and consequences of complex karyotype evolution in p53 driven acute myeloid leukemia"
Institution: Memorial Sloan-Kettering Cancer Center
Award Program: Fellow
Sponsor(s) / Mentor(s): Scott Lowe, PhD, and Dana Pe'er, PhD
Cancer Type: Blood
Research Area: Genomics
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