Acute myeloid leukemia (AML) refers to a group of disorders that are
also known as blood cancer. AML is an aggressive disease of malignant
immature blood cells which, if left untreated, almost always causes the
death of the affected patient.
The established method of treatment is
the use of a combination of various chemotherapeutic agents. However,
dependent on the genetic subtype and the age of the patient, only about
half of those with AML respond to this kind of treatment.
‘Targeted epigenetic approach for the treatment of aggressive forms of leukemia has been developed by cancer researcher from Mainz.’
In leukemia cells it is often the case that genes are reactivated
that, in physiological terms, mediate the self-renewal of blood stem
cells. In a common subtype of acute myeloid leukemia, this abnormal
activation of such self-renewing genes is apparently caused by
structural modifications of the DNA packaging.
In turn, these
modifications are caused by two specific proteins of the so-called
chromatin regulator group, on which leukemia cells are dependent. These
discoveries were made by oncologist Dr. Michael Kühn from the Department
of Internal Medicine III, which is a part of the University Center for
Tumor Diseases (UCT) at the Mainz University Medical Center, in a
collaborative effort with researchers from the Memorial Sloan-Kettering
Cancer Center in New York and Harvard University in Boston.
researchers were able to demonstrate that a targeted drug-based
inactivation of the two chromatin regulators will interrupt the
self-renewing program, thereby causing leukemia cells to revert to
normal blood cells. The results have been published in Cancer Discovery
The goal of current research is thus to develop more efficient and
less toxic forms of treatment. To achieve this, Dr. Michael Kühn of the
University Medical Center of Johannes Gutenberg University Mainz (JGU)
has been collaborating with the work groups of Professor Scott Armstrong
in New York and Boston.
They built on the relatively recent scientific
discovery that changes to the "packaging structure" of DNA can
contribute to the development of cancers. These chemical modifications
particularly occur in the so-called histone proteins. These proteins are
responsible for the coiling of DNA in mammalian cells. Various chemical
modifications of these histone proteins will result in an increase or
decrease in the relevant gene activity. DNA wrapped around histones is
also called chromatin. Accordingly, the proteins writing, reading, or
removing the chemical modifications of histones are called chromatin
These modifications represent a layer of information that can be
passed from a parent cell to a daughter cell but is not encoded in the
DNA sequence. This field of research is therefore known as
"epigenetics". Medical research focusing on epigenetics is currently
trying to block the enzymes that regulate these changes thereby
silencing cancer promoting genes. One example of such research is the
study undertaken by Dr. Michael Kühn and his colleagues. Its subject is
the NPM1-mutated (NPM1mut) AML subtype, which is one of the most common
leukemias in adults under the age of 60 years.
It has been known for quite some time that NPM1mut AMLs are
associated with the activation of the so-called homeobox (HOX) stem cell
genes. The HOX genes play a fundamental role in the developmental
processes of organisms. They are particularly responsible for the
self-renewal of blood stem cells. It has been assumed that activation of
HOX genes turns normal blood cells into leukemia cells by initiating
stem cell-like self-renewal.
However, it has been unclear to date how
this activation occurs. In an attempt to answer this question, the
researchers undertook a targeted manipulation of leukemia cell DNA in
the lab. Using a relatively new technology called CRISPR/Cas9, they
managed to accurately cut out specific DNA sequences from leukemia
cells. This enabled them to analyze the functioning of two proteins,
namely, the mixed lineage leukemia (MLL) protein and the disruptor of
telomeric silencing 1-like (DOT1L) protein.
Based on these experiments, the researchers were able to demonstrate
that the survival of NPM1mut leukemia cells depends on these two
proteins. Both proteins belong to a group of regulators that control
chromatin and thus an important structural component of the cell
The researchers then used two highly specific chemical agents
to block the specific functions of those proteins. While they were able
to block DOT1L directly using an inhibitor substance currently being
tested in a clinical trial for a different type of leukemia, a direct
drug-based inhibition of MLL proved impossible. The researchers
therefore inhibited chromatin binding of MLL using drugs that target
this protein indirectly.
Both drugs reduced the activity of the homeobox stem cell genes in
NPM1mut leukemia cells, while the combination of the two compounds
resulted in nearly complete inactivation of these genes. Following
combined exposure to the two substances, the leukemia cells underwent
substantial changes and, to the surprise of the researchers, started to
turn back into normal blood cells.
The described approach represents the first molecularly targeted
treatment of NPM1mut leukemias by reversing a key mechanism of
leukemogenesis and builds a basis for future clinical trials assessing
these drugs in patients with NPM1mut leukemia.