September is National Blood Cancer Awareness Month, a time to raise awareness of blood cancers and the research needed to better prevent, diagnose and treat these diseases. At the University of Cincinnati Cancer Center, researchers are working to understand the biology that drives blood cancers and translate those discoveries into new approaches that may improve outcomes for patients in Cincinnati and beyond.

Blood cancers are a diverse group of diseases that develop in blood-forming tissues, such as the bone marrow, or in cells of the immune system. The three major categories include leukemia, lymphoma and multiple myeloma, with many different subtypes within each category. Together, these diseases represent a significant area of cancer research in the United States.

According to the NIH’s National Cancer Institute, an estimated 67,790 new cases of leukemia, 88,240 cases of lymphoma and 36,000 cases of multiple myeloma are expected in the United States. These cancers are also expected to account for approximately 23,910, 21,070 and 10,850 deaths, respectively.

While advances in treatment have transformed care for many patients, researchers continue to face significant challenges, particularly when blood cancers return or become resistant to treatment.

Understanding What Drives Blood Cancer

“Blood cancers are a diverse group of diseases, and understanding their biological differences is essential to developing more effective, personalized treatments,” said Courtney Jones, PhD, program leader of the Pediatric Oncology Research Program at the Cancer Center.

Courtney Jones, PhD Program Lead, Pediatric Oncology Research Program University of Cincinnati Cancer Center

One of the greatest challenges researchers are working to address is treatment resistance and relapse. Even when treatment successfully eliminates most cancer cells, a small population of cells may survive and eventually lead to recurrent disease.

“Despite major advances in targeted therapies and immunotherapy, relapse and treatment resistance remain among our greatest challenges,” Jones said. “Researchers are working to identify the unique vulnerabilities of these cells while developing treatments that spare normal blood-forming stem cells and minimize long-term toxicity.”

Addressing these challenges requires collaboration across multiple areas of research. Scientists study the fundamental biology of cancer cells in the laboratory, while translational researchers work to determine how those discoveries can be applied to patient care and clinical researchers evaluate new approaches in clinical trials.

“Ultimately, our goal is to translate discoveries in cancer biology into therapies that prevent relapse and improve both survival and quality of life for patients,” said Jones. 

Advancing Precision Medicine in Blood Cancer Research

Blood cancer research is rapidly evolving as researchers gain a more detailed understanding of the genetic and molecular features that distinguish one cancer from another — and even distinguish individual cancer cells within the same patient's disease.

Across the United States, researchers are increasingly using genomic, single-cell and multi-omic approaches to understand this complexity. These technologies can help identify genetic mutations, cellular characteristics and biological pathways that may make cancer cells particularly vulnerable to certain treatments. This growing understanding of cancer biology is also helping advance precision medicine, using information about an individual's cancer to identify treatments that may be most appropriate for that disease.

Recently published in Blood, Linde Miles, PhD, and her team illustrated how these approaches can provide a more detailed view of leukemia biology. Researchers analyzed over 600,000 cells from 43 samples representing 32 patients with NPM1-mutated acute myeloid leukemia (AML) to examine how genetic changes shape leukemia cell states as the disease evolves.

Linde Miles, PhD Member, Signaling Networks & Metabolic Pathways Research Program University of Cincinnati Cancer Center

This study found that epigenetic mutations, including changes involving DNMT3A, TET2 and IDH1/2, can contribute to distinct cellular trajectories and immunophenotypes, while signaling alterations involving the FLT3/RAS pathway were associated with greater clonal complexity at relapse and shorter overall survival. Importantly, the findings demonstrate that a patient's AML genotype and the characteristics of individual leukemia cells are closely connected and can change over time, including during treatment and relapse.

These findings highlight the value of looking beyond bulk genomic profiling to examine individual cells and their changing characteristics. By integrating genetic, epigenetic and cellular information, researchers may be better able to identify high-risk leukemia clones, understand treatment resistance and develop more precise strategies for patients whose disease changes over time.

At the same time, immunotherapy and cellular therapies are expanding the ways researchers can target blood cancers. Treatments such as CAR T-cell therapy and bispecific antibodies harness or redirect the immune system to recognize and attack cancer cells. Researchers continue to study how these therapies can be used in more patients, how they can be combined with other treatments and how resistance can be overcome.

These national advances are helping shape research at the University of Cincinnati Cancer Center, where investigators are studying blood cancers from multiple perspectives.

“At the Cancer Center, leukemia research is focused on understanding why leukemia develops, why certain leukemia cells survive treatment and how those cells can be targeted to prevent relapse,” Jones shared. “Our researchers are studying the metabolic, genetic and signaling dependencies that allow leukemia stem cells to survive, while also investigating how leukemia changes over time.”

Leukemia stem cells have characteristics that allow them to persist despite treatment and can contribute to disease recurrence. As the cells acquire additional mutations, different populations of cells, or clones, can emerge within the same disease. Understanding how these mutations interact may help explain why some leukemias become more aggressive or resistant to treatment.

Cancer Center researchers are approaching these questions using a range of research strategies, including functional genomics, RNA biology, metabolism, drug discovery and precision medicine. The goal is to identify previously unrecognized vulnerabilities in leukemia cells and determine how those vulnerabilities could be used to develop new treatments for adults and children with high-risk or relapsed disease. One example of this work comes from research examining the role of cellular metabolism in acute myeloid leukemia (AML), a type of leukemia that develops in blood-forming cells. 

Investigating Treatment Resistance and Relapse in AML

Recently published in Blood, researchers alongside Jones identified a previously unrecognized vulnerability involving glutaredoxin 2 (GLRX2) a protein involved in regulating cellular redox balance and mitochondrial function. The study found that GLRX2 helps regulate mitochondrial function through a process called protein glutathionylation. Disrupting this pathway impaired the survival of acute myeloid leukemia (AML) cells while having less effect on normal blood-forming cells. Researchers also found that reducing GLRX2 increased the leukemia cells' sensitivity to cytarabine, a chemotherapy drug commonly used to treat AML.

“These findings point to mitochondrial redox regulation as a potential therapeutic vulnerability in AML and suggest that targeting this pathway could eventually help researchers develop strategies to overcome treatment resistance,” explained Jones.

In another study, Jones and a team of researchers explored whether measurable changes in the blood can provide insight into how a patient's AML may respond to chemotherapy. Also published in Blood, researchers analyzed plasma samples from 231 patients with newly diagnosed AML and examined circulating lipid profiles. The researchers identified a lipid signature associated with chemotherapy resistance and survival, including a specific sphingomyelin species that independently predicted outcomes in a validation group.

“The findings demonstrate how metabolomics and lipidomics — approaches that examine the small molecules and lipids present in biological samples — can provide information about the biological differences between AML cases,” Jones shared.

This type of research could ultimately contribute to the development of minimally invasive biomarkers that help researchers identify patients at greater risk of treatment resistance and better understand the metabolic characteristics associated with aggressive disease.

Understanding treatment-resistant leukemia is also the focus of one of Jones’ active grant-funded projects. “Interrogation of Glutathione Biology in Relapsed Acute Myeloid Leukemia Stem Cells” is focused on understanding why leukemia stem cells survive therapy and contribute to relapse in AML, with particular attention to glutathione (GSH), a molecule that helps regulate cellular redox balance and protein function.

“Relapse remains a major cause of death in AML, and effective approaches to specifically eliminate relapse-driving leukemia stem cells are limited,” Jones said. “We are investigating how glutathione metabolism and protein S-glutathionylation change in relapsed AML and whether those changes create vulnerabilities that could be targeted therapeutically.”

By identifying metabolic and protein-regulatory mechanisms associated with relapsed disease, the research could uncover potential therapeutic targets and biomarkers associated with treatment resistance. More broadly, it may help establish glutathione biology as an important area of leukemia metabolism and provide a framework for translating metabolic vulnerabilities identified in leukemia stem cells into new treatment strategies. 

From Research Discovery to Patient Care

The work being conducted at the University of Cincinnati Cancer Center reflects a broader evolution in blood cancer research: moving beyond treating blood cancers as single diseases and toward understanding the biological differences that make each cancer unique.

Researchers are examining cancer cells at increasingly detailed levels — from individual mutations and signaling pathways to cellular metabolism and interactions within the bone marrow environment. These discoveries can provide new opportunities to develop targeted therapies, identify biomarkers and understand why some cancers respond to treatment while others persist.

At the Cancer Center, researchers are also working to move promising discoveries from the laboratory toward clinical testing.

“The Pediatric Oncology Research Program, and really the Cancer Center overall, is increasingly focused on more rapidly moving discoveries from the laboratory into clinical trials, with the goal of developing treatments that are more effective, less toxic and ultimately capable of preventing leukemia relapse,” Jones explained.

As blood cancer research continues to advance nationally, discoveries made in laboratories and clinical settings across the country are contributing to a growing understanding of these complex diseases. At the Cancer Center, researchers are adding to that work by investigating the fundamental biology of leukemia and identifying vulnerabilities that could lead to new approaches for patients with high-risk and relapsed disease.

During Blood Cancer Awareness Month, these efforts highlight not only the challenges that remain but also the importance of continued research — connecting discoveries in cancer biology with the ultimate goal of improving treatment and outcomes for people affected by blood cancer.