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.
Sources:
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.
<http://www.nature.com/nature/journal/v506/n7488/full/nature13056.html>.
