Why a Common Leukemia Drug Works for Some Patients—and Not Others

A new study from Columbia University researchers may finally explain why a leukemia drug that works well in some patients has failed in others—and points to a new way that could make it more effective. 

The drug, called ATRA (all-trans retinoic acid), has long been used to treat a specific form of leukemia. However, clinical trials testing it in other types of leukemia have shown mixed results. Now, a team of scientists led by Stavroula Kousteni, PhD, have discovered that the key to whether ATRA works or not may lie not in the cancer cells themselves—but in the cells that surround and support them. 

Understanding the niche, the tumor’s neighborhood

While much of cancer research focuses on mutations in tumor cells, increasing evidence shows that the surrounding microenvironment—or “niche”—can play a powerful role in cancer progression. 

“We’re working to better understand the environment that allows these malignant cells to thrive,” says Kousteni, associate director for basic research and director of the Edward P. Evans Center for Myelodysplastic Syndromes (MDS) at Columbia University. “And we’re showing that the niche itself can be both a biomarker for precision therapies and a therapeutic target.” 

The researchers focused on a signaling protein called β-catenin, which can become abnormally active in osteoblasts, the bone cells that help build and maintain bone. They found that this abnormal activity—called osb-β-catenin activation—was present in nearly 40% of patients they screened who had acute myeloid leukemia (AML) or its early-stage precursor, myelodysplastic syndrome (MDS). These patients also had worse outcomes, suggesting this bone-driven signal plays a powerful role in how the disease behaves. 

Interestingly, when the team searched for an existing therapy that targets this pathway, they found ATRA, and delved into better understanding how ATRA works, not just on the cancer cell, but also in the surrounding niche. 

ATRA targets the tumor microenvironment, not blood cells

Utilizing RNA sequencing data and mouse models, the team discovered something unexpected: ATRA inhibits β-catenin signaling in osteoblasts, reducing JAG1 expression and downstream Notch1 activation in nearby hematopoietic cells. This indirect effect—targeting the niche rather than the blood-forming cells—offers a new explanation for why ATRA has shown inconsistent effects in past AML trials.  

ATRA’s effects were also independent of common genetic mutations that are drivers of MDS and AML such as TP53 or TET2—suggesting that targeting the niche could help overcome resistance linked to genetic diversity in myeloid cancers. 

In normal settings, the JAG1–Notch1 pathway helps control cell behavior. But in cancer, like leukemia, abnormal activation of this pathway can drive uncontrolled growth or prevent cells from maturing into healthy blood cells. The researchers found that ATRA inhibits JAG1 expression in osteoblasts, disrupting the tumor-supportive microenvironment. 

“Our data show that ATRA doesn't need to hit the cancer cell directly—it works by changing the environment around it,” explains Ioanna Mosialou, PhD, first author of the study. 

They reasoned that JAG1 could be a potential downstream therapeutic target. The researchers developed and tested a humanized anti-JAG1 monoclonal antibody, which similarly interrupted niche signaling and amplified the therapeutic effects in preclinical models. 

Expanding options with niche-targeted therapies 

Although these findings have not yet been tested in clinical trials, the study lays important groundwork for a new kind of therapy—one that focuses on the cancer’s environment rather than the cancer cells alone. 

“We’ve identified a vulnerability in the tumor-supportive microenvironment,” says Kousteni. “And we’re showing that this environment could be reprogrammed in more targeted and perhaps less toxic therapies for patients.” 

Co-author Azra Raza, MD, clinical director of the Edward P. Evans Center for MDS at Columbia, emphasizes the clinical promise. “This work opens up a therapeutic avenue that could complement existing treatments and potentially improve outcomes for patients who don’t respond to current options.” 

The researchers envision future strategies that use biomarkers of niche activity—such as β-catenin signaling in osteoblasts—to identify patients most likely to benefit from niche-directed therapies. 

While more work is needed before these insights reach the clinic, the study offers a powerful reminder that cancer’s success isn’t just in its genes—it’s also in its surroundings.