Blood Cancers

Current Projects
Stephen 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: "Targeting aberrant signaling pathways in myeloproliferative neoplasms"
Institution: Washington University
Named Award: Doris Duke
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Daniel Link, MD
Cancer Type: Blood
Research Area: Signal Transduction
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
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
William Razzell, PhD

Dr. Razzell [HHMI Fellow] is using cell biological, molecular genetic, and biophysical approaches to understand how cell-derived mechanical forces contribute to tumorigenesis through the modulation of cellular signaling pathways. One pathway that is responsive to mechanical forces is the Hippo pathway, which prevents excessive tissue growth during development. Characterizing how cell-derived forces control normal Hippo signaling will provide insight into the mechanisms by which Hippo pathway misregulation contributes to tumor progression.

Project title: "The role of tension in Hippo pathway signaling"
Institution: Memorial Sloan Kettering Cancer Center
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Jennifer A. Zallen, PhD
Cancer Type: Blood, All Cancers
Research Area: Developmental Biology
Neel H. Shah, PhD

Dr. Shah aims to elucidate structural details of the signaling enzyme ZAP-70, found primarily in immune T cells. Expression of ZAP-70 in other immune cells, B cells, however, is associated with chronic lymphocytic leukemia. Furthermore, loss of ZAP-70 function causes severe combined immunodeficiency; an impaired immune system can increase a patient's susceptibility to tumor development. His research on ZAP-70 structure and function will help understand how this enzyme differs from related signaling enzymes, thereby laying the groundwork for the development of ZAP-70-specific therapeutics.

Project title: "Interrogating ZAP-70 substrate recognition using high-throughput mutant screening"
Institution: University of California, Berkeley
Award Program: Fellow
Sponsor(s) / Mentor(s): John Kuriyan, PhD
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 RM 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): Glen Raffel, MD, PhD
Cancer Type: Blood, Other Cancer
Research Area: Experimental Therapeutics
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