- Chronic Myelogenous Leukemia
or sometimes known as Chronic Myeloid Leukemia
is a type of cancer where white blood cells
are mass produced in the blood.
These cells tend to be of the myeloid stem cell lineage
and because this is a chronic leukemia,
the cells we see in the blood stream tend to be
the more maturer type of blood cells
as opposed to an acute leukemia
where you have more immature cells in the blood stream.
This type of cancer occurs when a very specific mutation
happens where a gene that sits on chromosome 22,
that's called the BCR gene.
The BCR gene is shuffled so that it sits next to
a gene on chromosome nine
that's called the ABL or the ABL gene.
This defect is known as a translocations,
so we write translocation of a piece of chromosome
nine onto chromosome 22 that for the purposes of drawing
here will look something like this
where the BCR gene sits on the ABL gene
and they're attached together.
This new protein is a type of receptor tyrosine kinase
that's constantly on, telling cells that they should
keep on dividing, which is the whole premise of cancer.
You're making more cells than you need.
In fact, this translocation that puts a piece of
chromosome nine on a chromosome 22
produces a new type of chromosome altogether
that's called the Philadelphia chromosome.
Named for the university it was discovered at.
But the problem here is that now we're going to be
producing a whole bunch of white blood cells
we don't need.
So I'm drawing here the bone marrow,
and as you might recall, one of the first things
that's produced here is something
that's called a pleuripotent.
Meaning that something that has
the potency or the ability to make plural or many things
hematopoietic, meaning related to the blood stem cell.
Pleuripotent hematopoietic stem cell.
This can produce two different lineages.
I'll draw them out this way and we're not focusing so much
on this lymphoid stem cell lineage here,
so I'll just draw it off to the side.
But let's pay better attention here
where we have the myeloid stem cell.
As you know there are a variety of things
that could be produced here, so I'm just gonna
draw them out here, but not name all of them.
But recall it's these types of cells right here,
these white blood cells that we'll see
being produced excessively in Chronic Myelogenous Leukemia.
Because the defect is really high up, like around here
is where the mutation occurs,
we'll tend to see an irregular or an unusual amount
of platelets or even red blood cells as well.
That translates into a couple of key signs and symptoms.
Now Chronic Myelogenous Leukemia or CML
as it's sometimes referred to has three distinct phases
that have different signs and symptoms.
First, there's the chronic phase.
In the chronic phase, about 90% of patients
are asymptomatic, so without any symptoms.
Asymptomatic when they're diagnosed,
but later in this phase you can have some signs and symptoms
such as abdominal fullness, due to the fact
that excess platelets or other white blood cells
that are being made have to go to your spleen
to get processed or even destroyed if there's too many
defective ones causing the spleen to become big
or for you to have something that's called splenomegaly.
Splenomegaly, and the same thing can happen to your liver
as you have a higher basal metabolism
because of all the extra cells you have
in your blood stream.
When your liver gets big, we call that hepatomegaly,
so in total you could have Hepato-splenomegaly.
Other than the abdominal fullness,
a common symptom is having a fever
and this is mainly due to having an increased number
or a white blood cell count
because as I mentioned, that means that you're going to have
an increased basal metabolism,
which is just your metabolism at rest.
The chronic phase will progress,
and the next step would be what's called
the accelerated phase.
The accelerated phase and it's called the accelerated phase
because you are more rapidly making cells
and often times these are defected cells.
Those that don't actually work correctly
and this is well illustrated when you consider
the platelet because these patients
can have bleeding and it's because platelets
are supposed to clot and make sure you don't bleed
when you're cut, but if you're platelets are not working,
you will bleed more and these can manifest
as petechiae, which are just small dots
that you might see, which is bleeding
from your vessels or you can see
what are called ecchymoses.
Ecchymoses, which are just bruising
or bruises that occur when you even just bump
into things very lightly and so you'll have an accumulation
of blood under the skin that'll look like you hit it there
much more intensely than you actually had.
In the accelerated phase, you could also get a fever,
but this time, it's more likely due to
opportunistic infections,
which just means that microbes like bacteria,
or fungi, or viruses see an opportunity
to infect a human being or host because
the white blood cells are not functioning correctly
in the accelerated phase.
Finally, the most advanced phase someone can be in
is what's referred to as a, or the blast phase,
or even the blast crisis.
This is characterized by rapid immature cell production
which can cause you to have some pretty
significant bone pain.
Bone pain related to increased production
of myeloblasts in the bone marrow.
You can also have a fever and this is for the reasons
we've mentioned above, either from an opportunistic
infection or from having too many of these cells
in your blood stream.
Now these are just some things you would see
on phyiscal exam, but how would we make a more
definitive diagnosis?
Well, one of the simplest things you can do
is get a complete blood count,
which may show you that you have elevated
white blood cells in the blood stream
on the order of something like 50 to 200,000,
whereas you should have less than 12,000.
You can also take some of the blood
and look at it under a microscope and you'd see
on this peripheral blood smear that there are
a lot of leukocytes,
so you've got what's called leukocytosis,
which would look like this
where you've got a whole bunch of these white blood cells
and you can see they're very different from these guys,
which are your red blood cells
in your blood stream.
Let's minimize this guy and go back up
to this list right here.
One of the other things that you can see
that is considered a pretty slam dunk diagnosis
is a positive Fluorescent
In Situ Hybridization test
or a FISH that will light up to show you
that there is a Philadelphia chromosome present.
Now one thing I should mention at this point,
the Philadelphia chromosome,
it's present in about 95% of cases of CML,
so it's pretty good, but there are some cases
that you won't have it.
The translocation of taking the BCR gene
and putting it close to the ABL gene;
now that's present in 100% of CML cases,
so you don't have to have the full chromosome translocation
just the gene to get CML, but we check for this
because it's very commonly present with CML.
95% is a pretty good odds.
It would look like this right here.
This is a positive FISH, where you've got,
for example, green, perhaps lighting up the BCR gene.
Red lighting up the ABL gene and you can see
very interestingly here there's a green attached to a red
so that's the 9/22 translocation we're talking about.
Finally, the last thing or the thing we try to avoid to do
is what's called a bone marrow aspiration
where we inject a big needle into the bone marrow
and suck out some of the marrow and look at it
under a microscope where you will see
an increased number of myeloblasts.
Okay, so what do we do now to treat this?
Well, if you were with us for our conversation on
polycythemia vera or essential thrombocythemia,
you might recall some of these cytotoxic drugs
like Hydroxyurea or Interferon Alpha
and all they do is they make it difficult
to mass produce the white blood cell,
but perhaps the most important treatment
to know for CML is the use of a drug that's called
Imatinib, which is one of the greatest successes of science.
Long ago, scientists realized that the BCR-ABL translocation
produced this unusual receptor tyrosine kinase
that kept on telling cells, myeloid cells,
to keep on dividing and the idea was if we made a drug
that could block this receptor,
something that would come in here
and sort of bind the receptor and make it impossible
for it to communicate with the other types of enzymes
or proteins in a cell that signal
that signal that it's time to keep on dividing,
you could somehow prevent production of myeloblasts
and that's exactly what Imatinib does.
It prevents this unusual protein from working
and as a result, you can actually cure cancer, cure CML
from employing this drug and making it so that you don't
produce all these extra white blood cells.
This was an amazing accomplishment
because before Imatinib, the prognosis for CML
was pretty poor.
Most would be dead in three to five years without this drug,
but now when you use it, so with Imatinib,
90% are alive at five years.
Finally, coupled to Imatinib because you're gonna block off
production of this protein that is actually necessary
for division from time to time,
you would have to give this patient what's called an
allogeneic stem cell transplantation to make sure
they have the cells or the protein machinery
to continue dividing and producing white cells correctly.
CML's a pretty interesting disease
and I think what's great about it is that it really
illustrates the success of science,
kind of looking into what is the protein produced
from a defect and what we can do to generate something
to essentially cure cancer.