Blood Cancers

Current Projects
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
Neel H. Shah, PhD

Tyrosine kinases are enzymes that act as “on” and “off” switches for signals in cells and are important in regulating cellular activity, such as cell division. They can become mutated, stuck in the "on" position, and cause unregulated growth of the cell, which is a necessary step for the development of cancer. Kinase inhibitors have been developed as cancer treatments, but they have not been sufficiently effective and are susceptible to drug resistance.  Dr. Shah seeks to identify new activities and modes of regulation that distinguish oncogenic and non-oncogenic tyrosine kinases, with the goal of identifying more specific drug targets.

Project title: "Identifying divergent mechanisms of oncogenicity in tyrosine kinases"
Institution: Columbia University
Award Program: Dale Frey Scientist
Cancer Type: Blood
Research Area: Structural Biology
Melody Smith, MD

Bone marrow transplant (BMT) is a treatment approach where cells from a healthy donor are given to a patient with blood cancer who has not responded to other treatments. Unfortunately, there are risks to this procedure such as graft-versus-host disease (GVHD), which occurs if the cells from the donor attack the "foreign" patient tissue; this can cause serious organ damage and is life-threatening. Melody is investigating an approach to decrease GVHD while also maintaining the benefits of BMT, specifically graft versus tumor (GVT). She utilizes T immune cells from the donor and enables them to express a B cell marker, CD19; these cells can induce complete remissions in patients with CD19-positive leukemia and lymphoma. Administration of these cells following BMT mediates persistent GVT and decreased GVHD. Given that donor T cells are the culprits that cause GVHD, the finding of decreased GVHD in her model was paradoxical. She will now translate these pre-clinical findings to a clinical trial in order to benefit patients.

Project title: "CD19 targeted donor T cells improve graft versus tumor activity and reduce graft versus host disease"
Institution: Memorial Sloan Kettering Cancer Center
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Marcel R.M. van den Brink, MD, PhD
Cancer Type: Blood, Other Cancer
Research Area: Immunotherapy
Alexey A. Soshnev, MD, PhD

Dr. Soshnev [HHMI Fellow] studies how genetic information is packaged in the nucleus and how such packaging is interpreted by the cellular machinery. Changes in nuclear architecture may simultaneously affect the function of thousands of genes and are a hallmark of cancer. This research focuses on a family of small nuclear proteins termed "linker histones," which are thought to orchestrate higher-order folding of DNA in the nucleus. Understanding the molecular connection between the nuclear architecture and gene regulation will shed new light on the processes underlying oncogenic transformation.

Project title: "The study of linker histone H1 in transcriptional regulation and genome organization"
Institution: The Rockefeller University
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): C. David Allis, PhD
Cancer Type: Blood, All Cancers
Research Area: Chromatin Biology
Yadira M. Soto-Feliciano, PhD

Pediatric acute myeloid leukemia (AML) has the lowest survival rate among all pediatric cancers. MLL gene rearrangements (MLL-r) occur in about 20% of children diagnosed with AML. This subtype of leukemia is exquisitely sensitive to inhibition of the interaction between MLL and the chromatin adaptor Menin. Dr. Soto-Feliciano is combining genetic, genomics, and mouse modeling approaches to identify factors that regulate the function of Menin in MLL-r and non-MLL-r leukemia. The identification of cellular mechanisms that mediate the response to Menin-MLL inhibitor-based therapies (already in pre-clinical studies), will inform us about the molecular mechanisms driving acute leukemia. She anticipates that the results of these experiments will provide a better understanding of gene expression programs and chromatin landscapes governing the leukemic state. In addition, this project has the potential to identify novel dependencies that can lead to development of novel drug targets for the treatment of pediatric leukemia.

Project title: "Dissecting the role of Menin in acute leukemia"
Institution: The Rockefeller University
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): C. David Allis, PhD
Cancer Type: Blood, Pediatric
Research Area: Epigenetics
Sakiko Suzuki, MD

Despite many recent advances, today’s treatment of leukemia still relies on medications that have very toxic side effects and can cause death. Therefore, it is crucial to search for new types of therapies that directly target leukemia without harming the normal cells of the body. A gene called MPL encodes a protein found to be important for the growth and survival of a significant proportion of Acute Myeloid Leukemias (AMLs) and other blood diseases including Essential Thrombocythemia (ET), a malignancy affecting the platelet-producing cells of the bone marrow. Sakiko has been focusing on the function of a truncated variant of MPL produced by splicing out a section of the MPL RNA message used to make the protein. This variant, MPL-TR, opposes the function of MPL in cells; she believes that increasing MPL-TR in leukemia cells will suppress their growth. Anti-sense oligonucleotides (AONs) are very short segments of RNA or DNA that can be constructed to bind specifically to RNA messages in the cell, so no other genes are affected. By targeting AONs to the regions in MPL RNA important for splicing, she proposes that leukemia cells will make more MPL-TR, thus inhibiting their growth and survival. She will test a series of AONs targeting human MPL splicing, designed to enhance levels of MPL-TR. These experiments will provide the foundation for establishing a clinical trial with the novel, targeted AON. The principles founded by this project would also be broadly applicable for targeting splicing in other genes essential for multiple forms of leukemia and lymphoma.

Project title: "AON-directed alternative splicing as a novel therapy for leukemia"
Institution: University of Massachusetts Medical School
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Michelle A. Kelliher, PhD, and Peter E. Newburger, MD
Cancer Type: Blood, Other Cancer
Research Area: Experimental Therapeutics
Albert G. Tsai, MD, PhD

Dr. Tsai is developing next-generation diagnostics for low abundance cellular cancer samples. By measuring 40 or more markers simultaneously on individual tumor cells deposited on glass slides, he hopes to enable definitive diagnoses of blood and lymph node cancers without the need for invasive surgery or a histopathology laboratory. These methods will also provide a unique way to study these cancers, by merging traditional light microscopy with automated antibody-based multi-marker analysis.

Project title: "Diagnosis of hematologic malignancies from paucicellular aspirate material using highly multiplexed single cell analysis"
Institution: Stanford University
Award Program: Fellow
Sponsor(s) / Mentor(s): Sean Bendall, PhD
Cancer Type: Blood
Research Area: Pathology
Evan J. Worden, PhD

Dr. Worden examines how the decision to “turn on” or “turn off” genes is determined by a highly coordinated series of events that rely on the chemical modification of histone proteins. Misregulation of histone modification can cause a variety of human cancers. Dr. Worden is using structural biology and biophysical approaches to understand how the precise patterning of histone modifications - the “histone code” - is established. He plans to study the regulatory mechanisms that control histone methylation, which is important for the formation of leukemias.

Project title: "The mechanistic basis of crosstalk between histone H2B ubiquitylation and H3K79 methylation"
Institution: The Johns Hopkins University School of Medicine
Award Program: Fellow
Sponsor(s) / Mentor(s): Cynthia Wolberger, PhD
Cancer Type: Blood, All Cancers
Research Area: Biophysics
Yi Yin, PhD

Dr. Yin is using newly developed state-of-the-art single cell sequencing technology to examine how DNA repair mechanisms go awry and contribute to cancer initiation and progression, as well as response to chemotherapy. Cancer cells usually have characteristic loss-of-heterozygosity, copy number variation and other types of genome rearrangements. A better understanding of the molecular mechanisms, genomic and cell contexts and effects from different allele variants in DNA repair genes of each individual may help guide treatment approaches for many cancer types, including breast, skin, and blood cancers.

Project title: "Global analysis of DNA break repair by single-cell sequencing"
Institution: University of Washington
Award Program: Fellow
Sponsor(s) / Mentor(s): Jay A. Shendure, MD, PhD
Cancer Type: Blood, Breast, Skin, All Cancers
Research Area: Chromosome and Telomere Biology
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