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Theme 1 - Molecular biology of cancerIntroduction/leukemias – Schuringa – 21-09-2020
Cancer is often caused by alterations in our DNA: mutations can result in oncogenes and in non-
mutated form these are the proto-oncogenes and in tumor suppressors. They have an effect on
cellular behavior of cells, not only on genetics, but also epigenetics & metabolomics. It is a genetic
disease, but also epigenetics and metabolomics are important.
In some cases, tumors are not driven by gene amplifications, but by mutations, e.g. in the case of
bladder cancer driven by H-ras Mutations:
There can be point mutations. Point mutation in Ras gene (= signaling molecule that can shuttle
between active and inactive phosphate phase, 3 or 2 phosphates) This shuttle is controlled by signals
from the outside. Once a cell receives a signal →RAS GDP switch to RAS GTP → phosphate available
on downstream molecule → signaling is transferred from one
molecule to another.
1. Phosphate is negatively charged → conformational change.
2. But negative charge allows to couple two proteins to each
other. Negative can bound to positive. That together forms
the key lock of a domain (f.e. SH2) for signaling molecules.
If you have mutation of a single base pair → glycine into valine →
change conformation of binding pocket → favors binding of molecule
to GTP. These molecules are locked into an active state. One mutation
is enough! Aggressive proto-oncogene.
DNA can also be altered by amplification. A decrease of part of your chromosome can underly cancer
development. ErbB2/neu/Her2 is an important gene in breast cancer. Patient 4 has less DNA of this
gene than patient 1. Patient 1 has an amplification of this locus. You have multiple copies of this gene
(more DNA) This leads to more transcript (RNA levels increased), more protein. You see a lot of dots
→ this locus is amplified, multiple copies in our genome.
Pointmutations, amplifications and deletions. DNA can also be altered by chromosomal
translocation. Chromosomal translocation can arise in multiple flavors. Chromosome 8 and 14. There
can be a break point in chromosome 8 before the coding part of myc proto-oncogene. Separating the
promotor and regulatory elements that control myc expression from the real myc encoding part
itself. Chromosome 14 is also broken. Myc is positioned close to the IgH region, this region is very
active in lymphoid cells that produce immunoglobulins. Fusion → regulatory part on chromosome 8,
that normally regulate how much myc is
expressed, is exchanged with the highly active
IgH locus, that drives a lot of this expression.
So level of myc expression is much higher, this
is because regulatory elements are positioned
close to the proto-oncogene → resulting in
much more expression, while the gene isn’t
amplified. So you see just 2 alleles with the
FISH, 2 dots, but much higher RNA and
protein levels.
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,Chromosomal translocations resulting in altered function of proteins.
Chromosomal translocations where breakpoint is in coding region. Bcr-abl
protein give rise to chronic myeloid leukemia. Breakpoint in coding sequence of
abl gene and in bcr part 3 breakpoints. Fusion of chromosome 9 with 22 results
in new open reading frame, you get a new protein → bcr-abl protein that is
expressed. This protein contains part of abl and bcr.
Cancer is often caused by alterations in our DNA (oncogenes/tumor
suppressors):
1. Mutations in genes, without copy-number changes (point mutations in
RAS).
2. Genome amplifications resulting in enhanced expression of e.g. growth
promoting genes (MYC)
3. Chromosomal translocations resulting in enhanced expression of oncogenes:
a. Fusion to active promotors (MYC).
b. Fusion proteins with altered function (BCR-ABL).
c. Loss of negative regulation via microRNAs (let7-HMGA2). If the end of the gene is
lost during translocation→ negative regulation is lost, because in the chromosomal
break point, the negative regulation is lost.
4. Gene expression changes caused by epigenetic alterations.
How do we get mutations in our DNA?
• Exposure to chemicals, UV, etc.
• Inherited
• Bad luck. With each cell division, there is a lot of mutations generated → some not
corrected. With each transcription round → more mutations. Spontaneous… bad luck.
o Mutations can result in unwanted cell growth, on the other hand, without mutations,
we never get evolution. Trade-off between cancer and evolution.
Types of genes that can be mutated:
There is only a hand full of genes that can work as an oncogene → these are the genes that control
signal transduction. Signal transduction initiated by an input layer, an extracellular layer of growth
factors, ligand and cytokines that can bind to their receptors. Binding to receptors means
dimerization of receptors, so that they become activated and within the cytoplasm, adaptors,
enzymes, kinases that can be bound by receptors and activated by those receptors. Then RAS GDP →
GTP → Whole series of cascades activated resulting in activation of transcription factors. Bind to
enhancers and promotors of target genes and drive expression of these genes. These signaling
molecules can be mutated → so cancer is not a very different kind of biology or different state of
cells, it is normal physiology that is misused by cancer cells. The control is different!
In cancer, there are mutations in receptors or kinases that result in cell-autonomous kind of acting,
resulting in control of these very important process. So the machinery that is used to control growth
or adhesion is very much the same.
Normal versions of oncogene-encoded proteins often serve as important components of this
machinery.
Cancer is not different than healthy, it is just a cheeked a little bit different.
What kind of processes do we need to introduce in normal cell to get a tumor cell?
Number of process, of which should be altered to transfer normal cell into tumor cell → sustaining
proliferative signaling, if you start to proliferative more, cells and tissues sense this and then growth
suppressors are activated. As tumor cell, you want to prevent this: tumor suppressors. so evading
growth suppressors. Also avoiding immune destruction. Tumor cells inactive the immune system, or
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,‘don’t recognize signals’. With each cell division, telomere shortens, cells
enter a senescence state. Tumor cells don’t want that, they want to
divide. So bypass the senescence. So enabling replicative immortality.
Stem cells maintain telomeres at length. There is a similarity between
cancer cell and stem cell. They are quite similar. So inflammation, the
environment in which cells live. There is a lot of cells together that
generate the tumor. Part of that involves the induction of inflammatory
kind of environment. Tumor cells can deal with this, but healthy not. So
inflammation is important. Activating invasion & metastasis, inducing
angiogenesis, genome instability & mutation, resisting cell death,
deregulating cellular energetics. Something has to be altered of these
things, to become a tumor cell.
Potential exam question: name 3 hallmarks of cancer and describe how
mutations in these might contribute to cancer.
Hematopoietic system:
Hematopoiesis (formation of blood) is initiated by stem cells of the bone marrow. They can divide
into two daughter cells (asymmetric), one of cells is new stem cells, another cell that is a cell that
differentiate into a progenitor cells and give rise to other functional mature blood cells (immune
cells, blood platelets, white blood cells, red blood cells).
Blood system is active system, on a daily or hour or second, surprise how active this is. Few thousand
cells per second. Within in bone marrow environment, give rise to progenitor cell in a second, few
hundred thousand cells produced. These cells are short-lived, therefore need to be regenerated from
pool of stem cells in bone marrow. The stem cells that are needed to undergo the first cell divisions
and to provide hematopoietic system with progenitors. This first cell division is a rare and infrequent
cell division. Once a month, some even less. Now and then → asymmetric cell division → rise to
progenitors → divide massively. Driven motor in bone marrow. Stem cells has everything that a
cancer cell needs. The only thing, those cells don’t divide very often. Cancer where the cause not lie
in a cell extrinsic phenomena (UV, radiation), and where the
cancer do not evolve as a consequent of a germ line
mutation, which is also for leukemia, you are left with bad
luck.
In leukemia patients, there is a block in differentiation.
Shortage of functional mature blood cells. As a
consequence, you have an accumulation of immature blast
like cells, fill up bone marrow. These cells are not able to full
fill the functions that a normal blood system have. If you
have not enough blood platelets → problems with bleeding.
Leukemia: impaired differentiation and accumulation of immature blasts in the bone marrow:
• Not all leukemia patients have the same features. One subtype is acute lymphocyte
leukemia. Arise in the lymphoid compartment.
• Chronic lymphocytic leukemia. Arise in the lymphoid compartment.
• Acute myeloid leukemia. Arise in myeloid compartment.
• Chronic myeloid leukemia. In myeloid compartment.
Differences acute vs chronic lies in the speed which the diseases develop. Acute is very aggressive
and quick. Real differences at molecular basis, the genetics → diseases caused by different kind of
genetics alterations. AML is a disease that is not by bcr-abl, but other mutations.
• Myelodysplastic syndrome.
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, • Clonal hematopoiesis of indeterminate potential is disease state that is preceding MDS and
AML development later on. They are not sick, but genetics that are presetting the state for
AML of MDS.
We do know the players. 250 mutations in the DNA that are associated with leukemia. 5-15
mutations per patient. You need to accumulate a handful of those.
Mutations in the DNA:
• Translocations → PML-RARA. RARA is vitamin A receptor can fuse to PML gene, give rise to
fusion protein.
• Tumor suppressors → p53
• DNA methylation → DNMT, TET, IDH impact
• Activated signaling → kinases, RAS, phosphatases → transcription factors
• Chromatin modifiers → control histone modifications. Chromatin is wrapped around 8
histones → nucleosome. Nucleosome has tails that can be modified. You need enzymes to
put these marks on or remove or read. Editors, readers and writers. They are typically
mutated, resulting in changes in epigenome → transformation.
If you pick out an individual patient with 3 mutations and if you look across cohord of 200 → 1 with
this exact combination. All of the 200 patients are different, so this disease they really represent at
personalized entity, so personalized medicine is important.
There is a total of 250 mutations that give rise to
leukemia. A number of mutations together are
needed to drive transformation. Is there is an
order of events? Sudden mutations come early,
some late, or by change? Yes it matter! There is an
order of events!
Sequence all of the mutations along the longitudinal time line → early mutations arise in epigenetic
machinery. Epigenetic machinery is first mutated → epigenetic landscape change → additional
mutations kick in, these are the signaling molecules. So there is a order of events.
If there is an order of events and acute myeloid leukemia is an age related disease. Look at the
potential mutations in healthy elderly. Pre-leukemic mutations already found in healthy individuals.
There are mutations that arise with a high frequency. This are mutations in the epigenetic machinery,
same that we find in the preleukemic state of leukemia development. The presence of these
mutations predict whether or not individuals get leukemia, there is an increase in clone size.
Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate
oligoclonal hematopoiesis:
Young adults ~11.000 HSCs, 1275 actively producing blood. Hendrikje van Andel-Schipper → blood
was fine, at least not leukemic, but her blood was studied in detail → 65% of blood populated by 2
HSC clones. 2 HSC clones was able to give rise to 65% of her blood cells. So they really clonally
dominate. This tells us two things:
1. Stem cells are powerful cells. One stem cell is enough to make a new blood system.
2. A mutation arises that block differentiation → you would left without 65% of your blood. So
this is a risky situation. Good example of massive hematopoiesis.
Potential exam question: would you classify AML as a genetic or epigenetic disease? Explain why.
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