Embracing the Constant of Change in Translational Leukemia Research

The ocean can serve as an effective teacher.

Throughout a lifelong fascination with sailing, Michael Andreeff, MD, PhD, has learned much from his time out on the open water. Equal parts “freedom” and “challenge,” he said the sea teaches one “how to respect nature.”

One moment, you are pushing through 48 knots of wind amid a dark storm, calling the Coast Guard to help guide you back to the safety of land. The next, you are free to admire the warm vibrance of a spectacular sunset.

For Andreeff, the ocean’s unpredictable and dynamic nature is a metaphor for all areas of life. His favorite saying—as well as the name of one of his boats—is panta rhei, a doctrine from the Greek philosopher Heraclitus meaning that “everything flows,” and that the only constant in life is change.

Panta rhei doesn’t just mean acknowledging the endlessly flowing winds and water on a voyage off the coast. It means constantly moving in an ever-changing world and always developing new contributions in translational science across the oncology landscape.

“Change is a fundamental essence of the universe. I’m contributing to this change in a small way, but the world around me is also changing and affects me,” Andreeff reflected. “Change is not always positive, [yet] it is important and very motivating.”

Embracing this universal paradox—the consistency of change—has allowed Andreeff to continuously pioneer new advancements in leukemia and other malignancies and earn his title as a 2025 Giants of Cancer Care inductee in Translational Science.

Studying to Understand Humankind

Andreeff initially underwent clinical training and worked his first job as a resident at the University of Heidelberg Medical School in Heidelberg, Germany. He earned his MD in 1968 and a PhD in cell biology in 1976. A particular interest in leukemias had flourished based on the ability to observe the cancer cells under a microscope and a drive to answer some philosophical questions surrounding the disease.

“I [became] fascinated with leukemia, with the acuity of the disease, and the danger that it posed to patients. Patients with leukemias can die in a few days, and I was always interested in oncology, as it places the patient and the compassionate doctor at the interface of life and death,” Andreeff explained. “There was a fascination early on with the philosophical question, ‘What defines life and therefore its proximity to death? To be or not to be?’”

Andreeff pursued his medical studies to “better understand man.” Learning anatomy, physiology, and pathophysiology was one pursuit, but understanding patients on an existential level was his true aim. As a student, Andreeff attended psychology classes for 8 semesters, along with a bit of philosophy and theology, to form a more complete picture of humanity. He ultimately gravitated toward oncology, which he described as the most “extreme medical science at the interface of life and death.”

Following rotating internships in pathology, medicine, surgery, and gynecology and obstetrics from 1968 to 1970, Andreeff pursued a residency and internship in medicine and as a scientific assistant at Medical Policlinic in Heidelberg in 1970 to 1975, followed by a fellowship in hematology/oncology at the 1st Medical Clinic in Mainz, Germany, part of the University Medical Center Mainz, from 1976 to 1977. Along the way, he started a research lab as a first-year resident, which was pivotal in his development of flow cytometry and instrumental in being appointed the youngest faculty member in Internal Medicine in Germany (“Privat-Dozent”).

As part of his postgraduate training, Andreeff became a special fellow in the Department of Medicine at Memorial Sloan Kettering (MSK) Cancer Center, where he received a 1-year grant. Equipped with his own research lab, Andreeff continued to advance his career at MSK, advancing from an assistant professor to associate professor during his 13-year tenure there.

In 1990, he accepted the role as the chief of the Leukemia Section at The University of Texas MD Anderson Cancer Center (MD Anderson). After moving to MD Anderson, Andreeff continued to develop clinical leukemia therapy and his lab research while obtaining NCI-funded major program project grants alongside his colleagues. He would later step down as the leader of the Leukemia Section in 1995 to devote more time and resources to his research.

Today, Andreeff serves as a tenured professor of medicine in the Department of Leukemia and the Department of Stem Cell Transplantation and Cellular Therapy at MD Anderson. He is also chief of the Section of Molecular Hematology and Therapy, as well as the Paul and Mary Haas Chair in Genetics at his institution.

“I’ve been here for 35 years now. I don’t know how this happened. It’s an inspiring environment with wonderful colleagues and great opportunities,” Andreeff said. “In retrospect, time flies by.”

Paving a Way Forward in Leukemia and Flow Cytometry

Starting in the late 1980s, Andreeff developed an interest in studying cell death—apoptosis. The main players there, Andreeff said, were BCL-2 and p53. Under the auspices of an acute myeloid leukemia (AML) program project grant, he collaborated with researchers inside and outside his institution to develop a BCL-2 inhibitor.

According to Andreeff, these efforts culminated in the creation of venetoclax (Venclexta), which “changed the treatment of myeloid and lymphoid leukemias.” Work on the molecule began as early as 2000, which was accompanied by a series of publications on its application in AML and other diseases starting in 2006.¹ Years of work eventually led to the FDA accelerated approval in November 2018 of venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine for patients aged 75 years and older with newly diagnosed AML.² The agency later granted full approval to this treatment regimen for the same patient population in October 2020.³

As Andreeff put it, his team was the first to discover the benefits and the limitations of venetoclax-based therapy for patients with AML. The agent in combination with hypomethylating agents “completely changed AML therapy” for those who previously couldn’t be treated, achieving response rates of 70% to 90% and even higher for an older subset of patients. However, a portion of patients would become resistant to venetoclax, which inspired further research on additional targets to overcome resistance to this agent.

“Venetoclax resistance has now become, besides targeting TP53, the most critical issue in leukemia therapy, but we have made some real progress there,” Andreeff said.⁴ “I think we can translate some of it into the clinic soon.”

Work from Andreeff and his team also showed that the small molecule inhibitor sorafenib (Nexavar) could directly target FLT3-ITD in AML, which influenced the research of additional therapeutic strategies designed to target this mutation.⁵ Other efforts have focused on targeting FLT3-TKD, IDH1/2, and RAS mutations in leukemias.

Studying these alterations informed Andreeff’s combinatorial approach to treatment decision-making. Given that leukemias may have multiple types of mutations, Andreeff said that targeting only one molecular characteristic “will not cure anybody.”

“Venetoclax [is] a very good combination partner with chemotherapy with FLT3 mutations, IDH mutations, and others. In all cases, there was an increase in cure rates when we combined these targeted treatments with the—in a way, nonmutation-targeted—treatments,” Andreeff said, highlighting an example.

A first-year resident, and inspired by work on his MD thesis, where he measured DNA and RNA in 900 cells, which took 3 years, Andreeff pioneered the application of flow cytometry in leukemias and cancer research. He created the first flow cytometry laboratory at the University of Heidelberg in 1971 and began to spread knowledge of this technique in the ensuing years.

“One day, I saw a throwaway journal in Germany; some biophysicist had developed a machine that could measure fluorescence in 1000 cells per second,” Andreeff said. “I had one of my rare moments of drawing the right conclusions.”

A few months later, Andreeff organized the first flow cytometry meeting in Germany; within the next year, he put together the first European meeting dedicated to this technique. According to Andreeff, the big breakthrough in flow cytometry corresponded with researchers seeking to understand the ratio of CD4 and CD8 cells in the blood of patients with HIV. He noted that he pursued his work in flow cytometry, following a group of researchers led by Len Herzenberg who developed the Fluorescence-activated cell sorter (FACS) at Stanford University.6 As a result, Andreeff said that the development of flow cytometry became “critically linked to immunology.”

After relocating to the US in 1977, Andreeff continued to hone his craft in flow cytometry. He organized the first “Clinical Cytometry” conference and from 1990 until earlier this year, he oversaw the Flow Cytometry and Cellular Imaging Facility at MD Anderson, which is equipped with the “latest, hottest equipment.”

“It’s possible, today, to measure 50 or 100 features per cell, not just 1, 2, 5, or 10. That’s done by advanced cytometry and mass cytometry,” Andreeff said. “It’s not just [for] immune cells; we are looking at leukemic cells. Now, we’re looking at the interaction between immune cells, leukemic stem cells, and cells constituting the bone marrow microenvironment.”

Researching and Overcoming Microenvironment Resistance

Andreeff and his colleagues identified cells in the bone marrow—mesenchymal stem cells (MSCs)—that play a key role in cancers developing drug resistance. His team then worked to understand how these MSCs interacted with leukemic cells.

These observations inspired the concept of a systems biology of the leukemia microenvironment focusing beyond individual cells. This system, Andreeff said, aimed to elucidate how stroma cells, MSCs, T cells, natural killer cells, dendritic cells, macrophages, and other matter interacted with each other as part of an interconnected network.

According to Andreeff, his team discovered that within TP53-mutated leukemia, T cells could harbor the same mutation, rendering them inactive. This correlation clarified how immunotherapy agents harnessing a patient’s T cells could become ineffective in the case of TP53-mutant disease.

Another key observation Andreeff highlighted was how mitochondria migrate from cancer cells to stroma cells—or vice versa—traveling through nanotubes to sustain the life of malignant cells. He and his colleagues noted that these mitochondria can harbor their own mutations, which can subsequently transfer to T cells and contribute to another form of drug resistance.

“The cure of cancer will be in mitochondria, one way or another....Mitochondrial transfer, including mitochondrial mutation, impairs the function of the cells that are the recipients of these mitochondria,” Andreeff explained.⁷ “We will not cure cancer unless we cut off the supportive roles of the microenvironment.”

The biggest discovery in Andreeff’s lab, however, came from what he described as chance. Matus Studeny, MD, who was then a fellow in the Stem Cell & Bone Marrow Transplantation at MD Anderson Cancer Center, visited Andreeff in his lab and proposed that MSCs may have the ability to migrate from the bone marrow into solid tumors. Andreeff commented that Studeny’s idea was “ridiculous” but to “do it,” and he supported the work leading to the key discovery of a new biological property of the tumor microenvironment.

Andreeff and his colleagues discovered that MSCs could infiltrate solid tumors and form tumor-associated fibroblasts at the invasive edge of the tumor. Subsequent research based on this observation supported the conclusion that MSCs could serve as effective platforms for a novel cell therapy for cancer.⁸ Andreeff’s group would work to apply this strategy by injecting gene-modified MSCs into ovarian cancer and other types of solid tumors later down the line.

“The hope is that this will make a major dent in all kinds of immunotherapy of cancer, not just leukemia. Of course, the concept still needs to be translated into successful clinical trials,” Andreeff said. He noted that an initial clinical trial in ovarian cancer is set to launch in 2026. “We already have evidence that T cells, NK cells, and macrophages in mice are recruited into the solid tumor, based on gene-modified MSCs and they survive longer. But this is just the beginning. We will use other immunotherapies to enhance the effect. Our goal is to make immunologically ‘cold’ tumors very ‘hot.’”

Stadning on the Shoulders of Giants in a "Golden Age" of Oncology

Andreeff acknowledged that these advancements in antileukemia therapies, flow cytometry strategies, and microenvironment knowledge would not have been possible without the help of his contemporaries and those who came before him.

“Everything I talk about is done in collaboration and on the shoulders of ‘giants.’ I’m not the sole inventor of what I discovered. We are all standing on the shoulders of other people,” Andreeff said. This collaborative mentality is something he seeks to impart to a new generation of researchers who work under his guidance. Researchers should “try to understand basic science and work in teams.”

“Nothing is done outside teams. People may claim that they are the sole geniuses, [but] the giants are all standing on the shoulders of many people,” he said. “My work on BCL-2 would not have been possible without my colleagues Marina Konopleva, MD, PhD, and Bing Carter, PhD; the work on MSC without Matus Studeny, Frank Marini, PhD, and Sandeep Singh, PhD; the work on mitochondrial transfer without Yoko Tabe, MD, PhD; and most recently, work on MYC degradation without Yuki Nishida, MD, PhD.”

Andreeff highlighted the guidance of Bayard Clarkson, MD, an emeritus member of the Leukemia Service in the Department of Medicine at MSK, whom he described as a “leading leukemia expert in the world.” During Andreeff’s time at MSK, Clarkson did not mentor by giving him concrete projects or ideas; he mentored by serving as a role model and by his approach to science.

“He pushed us into molecular biology and stem cell research. I had my independent lab from the beginning in New York, and he became not just a mentor but also a friend,” Andreeff said regarding Clarkson. “Although he was a generation older, as an eminent physician-scientist, he inspired a generation of young doctors. Ever since, I am trying to do the same: inspire and help young academics to find their own ways.”

Today, Andreeff and colleagues look to move further beyond individual targeted therapies toward a systems biology approach to cure leukemias.

“We are extremely privileged not to live in the 1700s but in 2025,” Andreeff said. “Now, when you look especially at oncology, it’s mind boggling. Every month, there are new agents that obtain FDA approval. It’s a golden age, right now, for oncology and research. It is nice to be a part of it—a true privilege.”

References

1. Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006;10(5):375-88. doi:10.1016/j.ccr.2006.10.006
2. FDA approves venetoclax in combination for AML in adults. News release. FDA. November 21, 2018. Accessed July 31, 2025. https://www.fda.gov/drugs/fda-approves-venetoclax-combination-aml-adults
3. FDA grants regular approval to venetoclax in combination for untreated acute myeloid leukemia. News release. FDA. October 16, 2020. Accessed July 31, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-venetoclax-combination-untreated-acute-myeloid-leukemia
4. Pan R, Ruvolo V, Mu H, et al. Synthetic lethality of combined Bcl-2 inhibition and p53 activation in AML: mechanisms and superior antileukemic efficacy. Cancer Cell. 2017;32(6):748- 760.e6. doi:10.1016/j.ccell.2017.11.003
5. Zhang W, Konopleva M, Shi Y-X, et al. Sorafenib (BAY 43-9006) directly targets FLT3-ITD in acute myelogenous leukemia. Blood. 2006;108(11):255. doi:10.1182/blood.V108.11.255.255
6. Clark DL. A brief history of flow cytometry. Flow Contract Site Laboratory. Accessed July 31, 2025. https://fcslaboratory.com/a-brief-history-of-flow-cytometry/
7. Ishizawa J, Zarabi SF, Davis RE, et al. Mitochondrial ClpP-mediated proteolysis induces selective cancer cell lethality. Cancer Cell. 2019;35(5):721-737.e9. doi:10.1016/j.ccell.2019.03.01
8. Studeny M, Marini FC, Dembinski JL, et al. Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst. 2004;96(21):1593-1603. doi:10.1093/jnci/djh299