myeloid leukemia (AML) is a result of a combination of gene mutations, the
most common mutation being in the FLT3 (FMS-like tyrosine
kinase 3) gene.
mutant form of FLT3 increased levels of a transcription factor called
RUNX1, revealed a new study.
RUNX1, is a transcription factor with known tumor-suppressor function,
elevated levels of RUNX1, after being activated by mutant FLT3 induces
tumor suppressor protein which was thought to prevent acute myeloid leukemia
(AML) can actually promote a particularly deadly form of the disease.
research team in Germany state that targeting this protein could be an
effective treatment for certain AML patients.
‘Inhibiting a transcription factor (RUNX1) in combination with currently used FLT3 inhibitors, may be a promising target for treating acute myeloid leukemia.’
the United States, AML accounts for over 1% of all cancer deaths.
is a heterogeneous group of cancers triggered by genetic and epigenetic changes
that together lead to abnormal and excessive proliferation
hematopoietic stem cells in the bone marrow and their subsequent failure to differentiate
into white blood cells.
prognosis for AML is poor due to relapse and treatment failure.
is characterized by an overproduction of immature white blood cells (WBC),
called myeloblasts or leukemic blasts.
immature WBCs prevent formation of normal blood cells by crowding the bone
excessive in number, they spill out into the blood stream and circulate around
immaturity hampers their ability to function properly to prevent or fight
infection. It can also result in anemia due to shortage of red blood cells.
myeloid leukemia is sometimes called acute myelocytic, myelogenous or
15% of childhood leukemia cases are AML. This disease is more likely to affect
the older individuals, over the age of 60 years.
those diagnosed with AML, less than 6 % are younger than 20 years of age and
more than 55 % are 65 years or older.
2007, there were about 44,240 new cases of leukemia in the United States.
have slightly more chances of being diagnosed with AML compared to women.
One of the most common mutation that causes AML is in the gene encoding
the cell surface signaling protein FLT3. Patients with this mutation show poor
rates of survival.
the mutant form of FLT3 can promote proliferation of hematopoietic stem cells,
this mutation is not enough to block their differentiation into white blood
cell and trigger AML on its own, according to experiments in mice.
Increased Levels of RUNX1
Stocking and colleagues at the Heinrich-Pette-Institute, Leibniz Institute for
Experimental Virology in Hamburg noticed an increased level of a transcription
factor called RUNX1 in many patients carrying the mutant form of FLT3 also
was unexpected because up to 20% of AML patients carry mutations that
inactivate RUNX1, which is generally considered to be a tumor suppressor that
prevents the formation of leukemias," Stocking says.
experimented in mice, researchers found that reducing RUNX1 levels reduced the
ability of human AML cells expressing mutant FLT3 to form tumors. In contrast,
elevated RUNX1 levels allowed the human AML cells expressing mutant FLT3 to
hematopoietic stem cells that expressed mutation in FLT3 were highly
proliferative, and when co-expressed with RUNX1 blocked their differentiation
into white blood cells, thus resulting in AML.
FLT3 activates RUNX1 by
promoting the transcription factor's phosphorylation.
activated RUNX1 then blocks white blood cell differentiation, by inducing
another transcription factor called Hhex.
stem cells expressing both Hhex and mutant FLT3 also gave rise to AML, the
results show that though RUNX1 may suppress the initiation of AML but, after
being activated by mutant FLT3, it blocked white blood cell differentiation and
promote tumor development.
that can reverse this differentiation block may offer significant therapeutic
efficacy in AML patients with FLT3 mutations," says Stocking.
RUNX1 is toxic to leukemic cells but not to normal hematopoietic stem cells, so
inhibiting RUNX1 may be a promising target in combination with FLT3
inhibitors." Stocking added.
study, "RUNX1 cooperates with FLT3-ITD to induce leukemia," is
published online in The Journal of Experimental Medicine
- Acute myeloid leukaemia (AML) - (http://www.leukaemia.org.au/blood-cancers/leukaemias/acute-myeloid-leukaemia-aml)
- Carol Stocking et al. RUNX1 cooperates with FLT3-ITD to induce leukemia. The Journal of Experimental Medicine; (2017) DOI: 10.1084/jem.20160927