Blood Cancers

Current Projects
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
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Scott Lowe, PhD, and Dana Pe'er, PhD
Cancer Type: Blood
Research Area: Genomics
Jay F. Sarthy, MD, PhD

Dr. Sarthy is developing new easy-to-use and affordable methods for studying DNA packaging and epigenetics (modification of gene expression) in pediatric cancers with a special focus on diffuse midline gliomas and neuroblastoma. These methods may help explain the drivers of pediatric malignancies and allow clinicians to better monitor response to treatment with the goal of developing new drugs that restore the cell’s ability to package DNA correctly.

Project title: "Characterization of the epigenomic landscape of diffuse midline gliomas"
Institution: Fred Hutchinson Cancer Research Center
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): Steven Henikoff, PhD, and James Olson, MD, PhD
Cancer Type: Blood, Other Cancer, Pediatric, Brain
Research Area: Epigenetics
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
Catherine C. Smith, MD

Acute myeloid leukemia (AML) is one of the deadliest blood cancers. Mutations in the FLT3 gene are the most common of all mutations in AML and are associated with poor outcomes in both adult and pediatric patients. Despite the importance of FLT3 mutations in AML, we still do not understand the way in which FLT3 is regulated and the functional impact of novel FLT3 mutations identified in recent large AML sequencing studies. Drugs targeting FLT3 have been successful in achieving remissions in AML patients but are limited by the rapid development of drug resistance, particularly due to reactivation of abnormal cancer signaling through the oncogene RAS.  Dr. Smith [Richard Lumsden Foundation Clinical Investigator] proposes studies to better understand how mutations found in AML patients cause dysregulation of FLT3 function and how activation of RAS signaling contributes to drug resistance and AML development. Her goal is to cultivate novel treatment strategies to target FLT3 in patients that will optimize response rates and prevent disease relapse.

Project title: "Defining structure, function and therapeutic impact of oncogenic FLT3 mutations"
Institution: University of California, San Francisco
Named Award: Richard Lumsden Foundation Clinical Investigator
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Neil P. Shah, MD, PhD
Cancer Type: Blood
Research Area: Signal Transduction
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
Anthony D. Sung, MD

The human gut is home to trillions of microorganisms, collectively called the microbiota, which affect health and disease. For example, in patients receiving hematopoietic stem cell transplantation as treatment for leukemias, lymphomas and other blood cancers, disruptions in the microbiota have been linked to disease relapse, infections and reduced survival. To address these treatment complications, Drs. David and Sung are developing ways to manipulate the microbiota through prebiotics, carbohydrates that a patient can ingest to stimulate the growth and maintenance of various beneficial bacteria. The challenge is that each patient has different microbiota and therefore may respond differently to the same prebiotic therapy. They are developing approaches for personalizing prebiotic treatments for hematopoietic stem cell transplant (HCT) patients based on their individual gut microbiota. After validating their prebiotic personalization with a mouse model, they will test the safety and feasibility of this treatment in a Phase 1 clinical trial with HCT patients.

Project title: "Personalized prebiotics to optimize microbiota metabolism and improve transplant outcomes"
Institution: Duke University
Award Program: Innovator
Cancer Type: Blood
Research Area: Microbiology
Sakiko Suzuki, MD

Myelodysplastic syndromes (MDS) are a heterogeneous group of blood disorders characterized by abnormal maturation of the hematopoietic blood cells and premature death of these immature cells leading ultimately to bone marrow failure. Patients with MDS are also at increased risk of developing acute myelogenous and acute lymphoblastic leukemias. Currently available treatments for MDS include serial blood transfusions for refractory anemia, hematopoietic cell growth hormone therapy, and eventually chemotherapy and bone marrow transplantation. However, bone marrow transplants are not an option for some patients due to lack of a matched donor. Additionally, not all patients are eligible for this treatment because of significant risks for long-lasting and severe side effects. New effective treatments are therefore needed.

Mutations in mRNA splicing factors, including SF3B1 and SRSF2, are the most common genetic alterations found in MDS patients. MDS is associated with an inflammatory gene signature suggesting that chronic inflammation contributes to disease pathogenesis. Dr. Suzuki will test whether these mutations sensitize blood cells to necroptosis, an inflammatory form of cell death, resulting in systemic inflammation that contributes to MDS disease propagation. She will also ask whether inhibiting necroptosis can rescue cells with SF3B1 or SRSF2 mutations and allow them to mature normally. If she proves that necroptosis plays a significant role in MDS disease, her work could then be rapidly translated to benefit MDS patients by using necroptosis inhibitor therapies that are currently being tested in the clinic for other diseases. These studies could lead to novel therapeutic options for MDS patients.

Project title: "Inflammatory cell death pathways in Myelodysplastic Syndromes"
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
Christina M. Termini, PhD

Dr. Termini aims to improve the success of hematopoietic stem cell transplants, which are used in the curative treatment of the majority of patients with leukemia or lymphoma. Prior to transplant, patients must undergo radiation therapy to decrease the number of cancerous blood cells. In order for hematopoietic stem cells to effectively repopulate the blood and immune systems of the transplant recipient, the stem cells must reach the bone marrow where they can expand. Her research focuses on how radiation regulates the abundance of molecules called proteoglycans within the bone marrow and how this impacts stem cell repopulation following transplant. Using in vivo transplantation models and super-resolution microscopy techniques, she will visualize and quantify how proteoglycans regulate stem cell interactions with the bone marrow. Her aim is to identify molecular targets that can be used to accelerate patient recovery following transplantation. 

Project title: "Proteoglycan remodeling of the bone marrow niche regulates hematopoietic stem cell regeneration"
Institution: University of California, Los Angeles
Award Program: Fellow
Sponsor(s) / Mentor(s): John P. Chute, MD
Cancer Type: Blood, Other Cancer
Research Area: Stem Cell Biology
Shou-Wen Wang, PhD

Many blood cancers, including leukemia and multiple myeloma, arise when early blood-forming cells do not develop properly. These aberrant cell fate choices cause abnormal blood cells to grow and divide uncontrollably. By combining lineage tracing, single-cell RNA sequencing (scSeq), and computational analysis, Dr. Wang aims to first develop a theoretical foundation and then build computational pipelines that reliably infer the order of events in cellular differentiation from these datasets. The results of this research may empower other biologists to systematically map out cell fate choice in their preferred systems. Applying the tools developed here to study perturbed blood formation (hematopoiesis) may also accelerate progress in understanding blood cancers.

Project title: "Inferring cell fate choice from clonal and transcriptomic data, with application to hematopoiesis"
Institution: Harvard Medical School
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): Allon M. Klein, PhD, and Fernando Camargo, PhD
Cancer Type: Blood
Research Area: Systems Biology
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