Elvin Wagenblast, PhD

Research Update December 2024:

Dr. Wagenblast and his team have made significant progress towards understanding how and when NUP98-NSD1 leukemia develops, as well as identifying its weaknesses for new therapeutic approaches. Using advanced sequencing techniques, they have identified populations of leukemia cells that are resistant to current treatments, such as chemotherapy, and confirmed that these cells rely on specific pathways to survive and grow. They have found that a specific protein, PRDM16, plays a critical role in supporting growth and treatment-resistance of these leukemia cells by regulating their energy use. By disrupting this protein in their models, they have shown that leukemia cells stop growing and previously resistant cells become once again sensitive to chemotherapy. Based on the discovery of the role of PRDM16 in leukemia, Dr. Wagenblast and his team tested a drug, Venetoclax, which targets a survival mechanism in leukemia cells linked to energy production. This drug showed promising results, significantly reducing leukemia cell growth in preclinical models. Dr. Wagenblast’s findings provide the first evidence that Venetoclax, a drug already approved for other blood cancers, could be an effective treatment in NUP98-NSD1 leukemia, paving the way for future clinical trials in children with this devastating disease.

Research Update April 2024: 

Acute myeloid leukemia (AML) is a complex and diverse type of blood cancer that can differ greatly from one patient to another, partly due to various genetic changes. One particularly challenging form of AML is seen in children, where two genes, NUP98 and NSD1, merge to form a new, harmful protein. This type of AML is especially difficult to treat and has a high risk of not responding to standard chemotherapy. In fact, children with this form of AML, combined with additional mutations in another gene called Wilms tumor gene 1 (WT1), have a less than 10% chance  of being disease-free after four years, illustrating that novel treatments are desperately needed for these children. 

To better understand and fight this type of leukemia, Dr. Wagenblast created a model that mimics this specific genetic change in human cells. He and his team discovered something very interesting: this harmful protein causes cancer in stem cells from postnatal umbilical cord blood but not in stem cells from adult bone marrow, helping to explain why this leukemia primarily affects children. Dr. Wagenblast’s research has three main goals: 

1. To understand how and why this genetic change leads to leukemia in children.
2. To figure out how mutations in the WT1 gene make this leukemia resistant to treatment.
3. To find new ways to treat this form of leukemia.

To date, Dr. Wagenblast has shown that these WT1 mutations make the cancer stem cells more primitive and harder to target with current treatments. His next step is to test a new treatment strategy using his model and samples from patients, to potentially shed light on why children are particularly vulnerable to this form of leukemia and to develop more effective treatment options for them in the future.  

Research Update December 2023:

Acute myeloid leukemia (AML) presents a formidable challenge due to its genetic heterogeneity, especially in pediatric cases where the fusion of NUP98 and NSD1 genes creates a particularly aggressive form of the disease resistant to standard chemotherapy. Children with this subtype, compounded with mutations in the WT1 gene, face dismal outcomes. The team's research aims to elucidate the mechanisms driving leukemogenesis in this context, focusing on understanding the role of the NUP98-NSD1 fusion and secondary mutations in WT1 in treatment resistance and disease progression. By utilizing a mouse model engrafted with human cells, they demonstrated that the NUP98-NSD1 fusion primarily affects stem cells from postnatal umbilical cord blood, shedding light on why this leukemia predominantly affects children. Additionally, the team found that WT1 mutations confer a more primitive state to cancer stem cells, making them resistant to standard therapies. The next steps involve testing novel treatment strategies using our model and patient samples across all developmental stages, aiming to decipher the developmental timing and mechanisms of these mutations, ultimately paving the way for more effective treatments tailored to pediatric AML patients.