Shreshtha and I are researching how a mutation in DNA-methyltransferase DNMT3a contributes to the development of Acute Myeloid Leukemia (AML). Though the existence of cancerous stem cells is still a very controversial topic, recent studies of acute myeloid leukemia provide evidence that neoplastic cells differentiate into different lineages of cell types.
Nature’s article, “Cancer: Persistence of leukaemic ancestors”, summarizes Slush’s findings that a DNMT3a gene mutation was not only common across AML patients, but carried at low rates in T cells, and other immune cells at the time of diagnosis. Since AML is characterized by cancerous myeloid cells and this DNMT3a mutation was found in non-myeloid cells of patients, it suggests that the mutation begins in the precursor cell that gives rise to blood cells of both lineages. Previously, it was believed that the gene NMP1 was the cause of AML, since it initiates the cancer in mice, but both mutations NMP1 and DNMT3a are present in these founder clone populations.
The chart below shows the routes of 3 intermediate stages of acute myeloid leukemia: undetected pre-leukemia, myeloid-cell dysplasia, and chronic myeloid leukemia. Each stage begins with hematopoietic stem cells, and only progresses to AML after the addition of secondary mutations. In the most common form, they are differentiated by DNMT3a mutation, but the cancer can also progress from a patient already having myeloid cell dysplasia, or mutation in BCR-ABL1.
In Hanahan and Weinberg’s article, “Hallmarks of Cancer: The Next Generation”, they explain how cancer stem cells take over the process of self-renewal for their growth, and hypothesize that the creation of cancer stem cells is related to the process of the EMT program, where epithelial carcinoma cells are converted to mesenchymal for dissemination. Similarly in AML, high levels of competitive self-renewal of DNMT3a mutant cells are what prevents normal self-renewal of the normal hematopoietic stem cell. Hanahan and Weinberg are focusing on cancer stem cells in tumors, and leukemia does not form tumors, but Slush’s research of hematopoetic stem cells in AML still supports the basic ideas behind the resistance of cancer stem cells.
This data is important because since AML is an aggressive, rapidly progressing disease, early detection and treatment are critical. If ancestors of precancerous cells in acute leukemia can be identified at an earlier stage in the cancer, by detecting a DNTM3a mutation, the precancerous cells can be treated before progressing into a secondary mutation. Additionally, cells with this mutation can be targeted and tracked specifically in therapies, to more effectively avoid remission from leftover traces of the disease.
The main questions this article raises are whether a mutation of DNTM3a by itself will lead to acute myeloid leaukemia, and whether it is the DNTM3a mutation that is initially responsible for starting the cancer’s growth. As we continue our research, we will delve further into the reasons behind hematopoietic stem cell differentiation.
Hanahan, Douglas, and Robert A. Weinberg. "Hallmarks of Cancer: The Next Generation."
Cell 144.5 (2011): 646-74. PDF file.
Potter, Nicola E., and Mel Greaves. "Cancer: Persistence of leukaemic ancestors."
Nature 12 Feb. 2014: 300-01. nature.com. Web. 13 Apr. 2014.