A research team led by scientists from Massachusetts General Hospital (MGH) and the Broad Institute 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,” said paper co-first author Peter van Galen of the Broad Institute's Epigenomics Program, the MGH Department of Pathology and Center for Cancer Research (CCR).
Co-lead author Volker Hovestadt, also of the Epigenomics Program, MGH Pathology, and the CCR, added, “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,” van Galen said. “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, Broad institute member, and Epigenomics Program director Bradley Bernstein, who is also with MGH Pathology and the CCR, added, “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 University, 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.”
Support for the study came from the National Institutes of Health, the National Cancer Institute, the National Human Genome Research Institute, the Ludwig Center at Harvard University, and other sources.