In a finding that challenges decades of assumptions about blood cancer, an international research team has shown for the first time that a specific subtype of diffuse large B cell lymphoma (DLBCL), which is the most common blood cancer in adults, is dramatically more lethal in women than in men. The study, led by the laboratory of Prof. Ari Melnick, Director of the Josep Carreras Leukaemia Research Institute, along with the laboratories of Drs. Wendy Béguelin from the New York University Grossman School of Medicine and Leandro Venturutti from the University of British Columbia, not only identifies the biological reason for this disparity but points to an existing class of drugs that could specifically protect female patients.

DLBCL affects hundreds of thousands of people worldwide each year. Although outcomes vary widely between patients, sex had never previously been identified as a driver of survival differences in this disease. By analyzing data from nearly 5,000 patients across 14 independent studies, the team found that women whose tumors carry simultaneous faults in two genes called SPEN and NOTCH2, had a more than fourfold higher mortality risk than men with the same mutations. Dr. Benedikt Pelzer, first author of this study commented:

"When we noted that women were doing far worse than men with these specific mutations, we knew we had to understand why. What we found was unexpected, that the X chromosome itself was the key."

Dr. Benedikt Pelzer, first author, Weill Cornell Medicine

The answer lies in one of the most fundamental differences between male and female biology. Women carry two copies of the X chromosome, and one is normally kept permanently switched off, a process partly controlled by the SPEN gene. When SPEN is damaged alongside NOTCH2, that silencing becomes unstable. Genes on the supposedly dormant X chromosome begin to wake up, including TLR7, a gene that when overactive, acts like a jammed accelerator for cancer cell growth and survival. In men, who carry only one X chromosome, this mechanism simply cannot occur.

Importantly, the researchers showed this is not driven by female hormones. The effect persisted in animals even after removal of the ovaries, confirming that the vulnerability is built into the chromosomes themselves — a genuinely new concept in understanding how sex shapes cancer biology.

"Sex differences in cancer have too often been attributed to lifestyle or hormones. This study shows the biology itself can be fundamentally different between men and women at the molecular level, and that this can be invisible unless you specifically look for it."

Dr. Leandro Venturutti, co-corresponding author, BC Cancer Research Institute / University of British Columbia, Vancouver

The discovery carries immediate therapeutic implications. The overactive TLR7 pathway that drives tumor growth in female patients can be blocked by drugs called IRAK inhibitors, which are already in clinical development for other conditions. In laboratory experiments and animal models, these drugs were significantly more effective at killing female tumor cells than male ones. A tumor model derived directly from a female DLBCL patient responded well, with growth slowing substantially over the course of treatment. Combining the IRAK inhibitor with standard chemotherapy enhanced the effect further, potentially allowing lower chemotherapy doses, which is especially important for the older patients who most commonly develop this disease.

"IRAK inhibitors are already in clinical trials. The path from this discovery to a treatment option for patients is shorter than it usually is in cancer research, and that urgency is something we feel strongly."

Dr. Wendy Béguelin, co-corresponding author, Weill Cornell Medicine / NYU Grossman School of Medicine, New York

The study also upends another long-held assumption about how this cancer develops. It had been thought that this subtype of DLBCL originates deep within the immune system's active response centers. The new data show it likely begins from a cell type that accumulates with aging and exposure to infections, and is closely associated with autoimmune diseases, consistent with a different developmental path, and potentially explaining why the disease is more common in older patients who may have had an undetected precursor condition for years.

"This work reframes the X chromosome from a bystander to an active driver of cancer biology in women. Combined with the discovery of a druggable target, it is a genuine paradigm shift, and a compelling argument for making biological sex a standard variable in how we design cancer trials going forward."

Prof. Ari M. Melnick, co-corresponding author, Director of the Josep Carreras Leukaemia Research Institute (Spain), and Gebroe Family Professor of Hematology/Oncology, Weill Cornell Medicine

About the study

"SPEN loss drives extra-follicular diffuse large B cell lymphoma with female-specific lethality and TLR pathway therapeutic vulnerabilities" was led by first author Dr. Benedikt Pelzer and conducted by an international team spanning the Josep Carreras Leukaemia Research Institute (IJC), Weill Cornell Medicine, BC Cancer Research Institute, Memorial Sloan Kettering Cancer Center, the University of Pennsylvania and other institutions. The study was supported by the US National Institutes of Health (NIH/NCI), Blood Cancer United®, the Lymphoma Research Foundation, the German Research Foundation (DFG), the German Cancer Aid, and the Canadian Institutes of Health Research (CIHR), among other funders.

Benedikt Pelzer, et al.; SPEN loss drives extra-follicular diffuse large B cell lymphoma with female-specific lethality and therapeutic vulnerabilities. Cancer Discovery 2026; https://doi.org/10.1158/2159-8290.CD-25-1458

What is DLBCL?

Diffuse large B cell lymphoma is a cancer of white blood cells. It is the most common form of blood cancer in adults, accounting for roughly 30% of all non-Hodgkin lymphomas. While many patients respond to standard treatment, around one in three does not achieve lasting remission and the disease remains life-threatening.