Rui Lu, Ph.D.Rui Lu, Ph.D., associate professor in the Department of Medicine, has been named the latest recipient of the school's Featured Discovery award. This recognition celebrates notable research contributions made by faculty and highlights the impact of their scientific advancements.

The study, titled “Epigenetic regulation of non-canonical menin targets modulates menin inhibitor response in acute myeloid leukemia,” was recently published in Blood and focuses on acute myeloid leukemia (AML) cells.

Acute myeloid leukemia (AML) is a cancer that impacts the blood and bone marrow, the soft tissue inside bones responsible for producing blood cells. In AML, the bone marrow generates abnormal white blood cells that fail to mature properly. Instead of developing into healthy cells that combat infections, these immature cells multiply rapidly and uncontrollably. This overproduction crowds out normal blood cells, leading to symptoms such as fatigue, frequent infections, and easy bruising or bleeding. Lu and his team are working to understand why these cells develop resistance to menin inhibitors.

Xinyue Zhou, UAB graduate student"Conducting this research was an incredible journey,” said first author Xinyue Zhou, UAB graduate student. “I am grateful for the collaborative effort that made this work possible and excited about its potential impact on the field of AML research.”

“These inhibitors target a crucial protein interaction in leukemia cells, but resistance often limits their effectiveness,” said Lu. “We discovered that leukemia cells can bypass menin inhibition by reactivating a unique set of genes through changes in gene regulation. Importantly, we found that combining menin inhibitors with BCL2 inhibitors can overcome this resistance, potentially improving treatment outcomes for patients.”

The Heersink communications team met with Lu to gain insights into the study and help raise awareness about both the research and the Heersink School of Medicine.

What compelled you to pursue this research?

AML remains a devastating disease with limited treatment options, and while menin inhibitors have shown great promise in clinic, resistance to these therapies is a major roadblock. My lab is dedicated to understanding the molecular mechanisms of drug resistance in leukemia with the goal of identifying vulnerabilities that can be targeted to enhance treatment efficacy. This research integrates epigenetics, functional genomics, and targeted therapies to advance precision medicine approaches for AML.

What was your most unexpected finding?

One of the most surprising discoveries was that resistance to menin inhibitors was driven by the reactivation of noncanonical menin target genes rather than the well-characterized leukemia-promoting genes. This suggests that leukemia cells can use alternative survival pathways, highlighting an unexpected layer of complexity in drug resistance. Our finding also revealed that BCL2 inhibition could selectively target these resistant cells, offering a new therapeutic strategy.

How do you feel your research will impact the science community?

Our work provides new insights into the epigenetic regulation of menin inhibitor response and drug resistance in AML. By identifying a distinct set of genes that leukemia cells exploit to bypass therapy, we offer a framework for studying resistance mechanisms in other cancers. Additionally, our findings support the rationale for combining menin inhibitors with BCL2 inhibitors, which could have a direct impact on clinical treatment strategies and inspire further research on targeted drug combinations.

What is your research’s relevance to human disease?

This research has direct clinical implications for AML, particularly in patients with KMT2A-rearranged and NPM1-mutated leukemia, who are currently being treated with menin inhibitors. By understanding why some patients develop resistance, we can propose rational combination therapies to enhance treatment response. The identification of BCL2 inhibition as a strategy to counteract menin inhibitor resistance suggests an actionable approach that could be tested in clinical settings.

When did you know you had an important discovery?

We realized the significance of our findings when we observed that leukemia cells resistant to menin inhibitors did not rely on the typical menin targets—a pattern that reflects what is seen in the clinic. Moreover, these resistant cells remained highly sensitive to BCL2 inhibition, suggesting that the resistance was due to a shift in cellular dependencies rather than an absolute failure of the therapy. This breakthrough highlighted a clear opportunity for a new therapeutic intervention.