Elvin Wagenblast, PhD

As Dr. Wagenblast nears the completion of his Young Investigator Award, he and his team have made major strides in pinpointing when and how NUP98-driven childhood AML begins, revealing insights that were not previously understood.

Their most recent work shows that this leukemia can only form in the very earliest blood stem cells, helping explain why it almost exclusively affects infants and young children. The team has continued their use of advanced single-cell tools to map how these leukemia cells fuel themselves, uncovering a strong dependence on fatty-acid and mitochondrial energy pathways. This led to the discovery that a protein called PRDM16 acts as a central “switch” that enables leukemia cells to survive treatment and remain aggressive.

Removing PRDM16 collapsed these survival programs, making the cells easier to eliminate. Based on these metabolic insights, the team continued testing of Venetoclax in expanded models and found that it was able to specifically eliminate leukemia-initiating cells, the rare cells responsible for relapse, when paired with chemotherapy. In parallel, they have begun analyzing samples from a young patient who relapsed after transplant to understand how the leukemia adapts over time. These new findings shed light on why this form of AML is so hard to treat and point to several promising therapeutic strategies now being prioritized for further testing.

Over the past six months, they have expanded their models to include a second high-risk fusion, NUP98-KDM5A, which occurs exclusively in infants, highlighting how early stages of blood development may influence how these cancers form and behave. They have also confirmed that leukemia cells rely on specific energy pathways regulated by a protein called PRDM16, and that disrupting this protein weakens the cancer cells and restores sensitivity to treatment. Building on these findings, the team tested an FDA-approved blood cancer drug, venetoclax, in combination with other therapies and saw a significant reduction in leukemia growth in patient-derived lab models. Notably, their research directly informed the treatment plan for a patient with NUP98-NSD1 leukemia, ultimately leading to a successful stem cell transplant and remission. These findings bring real hope for more effective, targeted treatments for children facing this aggressive form of leukemia.

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.

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:

• To understand how and why this genetic change leads to leukemia in children.
• To figure out how mutations in the WT1 gene make this leukemia resistant to treatment.
• 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.

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.