A research team led by Massachusetts General Hospital (MGH) investigators has assembled a detailed atlas of bone marrow cells from patients with acute myeloid leukemia (AML), an aggressive blood cancer that usually leads to death within five years of diagnosis. In their study, published in Cell, the team uses advanced technologies to detail both genetic mutations and gene expression in thousands of individual bone marrow cells from AML patients and healthy donors. Their results reveal specific tumor cell types that resemble normal stages of white blood cell development and also show a role for more differentiated tumor cells in suppressing an anti-tumor immune response.
“Acute myeloid leukemia is characterized by the accumulation of abnormal white blood cells in the bone marrow and blood of patients, and it has been known for decades that the disease comprises a variety of cell types that resemble normal developmental stages of blood cells,” says Peter van Galen, PhD, MGH Department of Pathology and Center for Cancer Research, co-lead author of the Cell paper.
Co-lead author Volker Hovestadt, PhD, also of MGH Pathology and the Center for Cancer Research, adds, “We used new technologies and machine learning to characterize almost 40,000 single cells from the bone marrow of AML patients and healthy volunteers. This approach is providing comprehensive insight into the different types of cancer cells and how they contribute to disease progression.”
The researchers used single-cell RNA sequencing to examine gene expression comprehensively in bone marrow cells from 16 AML patients and 5 healthy controls and incorporated a new strategy to determine which cells harbored characteristic AML mutations. The team then implemented a machine-learning algorithm to distinguish the malignant AML cells from normal cells in the tumor ecosystem. They found that AML cells could be classified according to their resemblance to six stages of blood cell development. Moreover, the specific mutations in tumor cells were found to control the developmental stages reflected and also appeared to induce aberrant patterns of gene activity and cell differentiation.
AML cells resembling the earliest stages of development – often called leukemia stem cells – are known to contribute to disease progression and relapse; and as expected, AML cells expressing genes associated with primitive developmental stages were prominent in patients with poor clinical outcomes. But the investigators also found evidence that more differentiated AML cells, not previously thought to have a role in tumor progression, can inhibit the function of T cells in the microenvironment, suppressing potential immune responses against the tumor.
“It is now clearer that genetic mutations can drive different cancer cell types that need to be specifically targeted with precision therapies, so our findings can guide personalized therapies to eradicate AML cells,” says van Galen. “Immune therapies that harness T cells have been less successful in AML, and our findings suggest that their efficacy could be improved by overcoming the inhibitory signals from differentiated tumor cells. Finally, better understanding of the abnormal regulation of developmental genes in leukemia stem cells may provide fundamental insights into the origins of this disease.”
Senior author Bradley Bernstein, MD, PhD, MGH Pathology and Center for Cancer Research adds, “This study would not have been possible without an incredible interdisciplinary team of cancer biologists, clinicians, technologists and computational scientists from MGH, the Ludwig Center at Harvard, the Broad Institute, and the Dana-Farber Cancer Institute. This collaboration to advance our understanding of cancer cell biology has the potential to significantly improve therapies for patients with what has been a very difficult to treat disease.” Bernstein is the Bernard and Mildred Kayden Endowed MGH Research Institute Chair and a professor of Pathology at Harvard Medical School.
Additional co-authors of the Cell paper are Gabriel Griffin, MD, Sofia Battaglia, PhD, and Julia Verga, MGH Pathology/Center for Cancer Research; Jennifer Lombardi Story and Timothy Graubert, MD, MGH Center for Cancer Research; Jason Stephansky, Timothy Pastika, Jon Aster, MD, PhD, and Andrew Lane, MD, PhD, Ludwig Center at Harvard Medical School; Marc Wadsworth II, Travis Hughes and Alex Shalek, PhD, Broad Institute; Geraldine Pinkus, MD, and Olga Pozdnyakova, MD, PhD, Brigham and Women’s Hospital; and Ilene Galinsky and Richard Stone, Dana-Farber Cancer Institute. Support for the study includes grants from the National Institutes of Health, the National Cancer Institute, the National Human Genome Research Institute and the Ludwig Center at Harvard University.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $925 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2018 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."
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