Chronic Leukemia – causes, symptoms, diagnosis, treatment, pathology

With chronic leukemia, “leuk” refers to
white blood cells, and “emia” refers to the blood; so in chronic leukemia there are
lots of partially developed white blood cells in the blood over a long period of time. These partially developed white blood cells
interfere with the development and function of healthy white blood cells, platelets, and
red blood cells. Now, every blood cell starts its life in the
bone marrow as a hematopoietic stem cell. Hematopoietic stem cells are pluripotent — meaning
that they can give rise to both myeloid or lymphoid blood cells. If a hematopoietic stem cell develops into
a myeloid cell, it’ll mature into an erythrocyte — or a red blood cell, a thrombocyte — or
a platelet, or a leukocyte — or a white blood cell, like a monocyte or granulocyte. Granulocytes are cells with tiny granules
inside of them — they include neutrophils, basophils, and eosinophils. If a hematopoietic stem cell develops into
a lymphoid cell, on the other hand, it’ll mature into some other kind of leukocyte:
a T cell, a B cell, or a natural killer cell, which are referred to as lymphocytes. Once the various blood cells form, they leave
the bone marrow, and travel around the blood, or settle down in tissues and organs like
the lymph nodes and spleen. Chromosomal abnormality in hematopoietic stem
cells that are destined to become leukocytes is the most common cause of chronic leukemia. Some examples of abnormalities include a chromosomal
deletion, where part of a chromosome is missing, a trisomy, where there’s one extra chromosome,
and a translocation, where two chromosomes break and swap parts with one another. Now there are two types of chronic leukemia. The first is chronic myeloid leukemia, CML,
which is caused by a particular chromosomal translocation that affects granulocytes. The second is chronic lymphocytic leukemia,
CLL, which is caused by a variety of chromosomal mutations that affect lymphocytes, in particular
B cells. Both CML and CLL cause cells to mature only
partially, and that’s a key distinction from acute leukemias where the cells don’t
mature at all. As a result, these abnormal, premature leukocytes
don’t work effectively, which weakens the immune system. In addition, the chromosomal changes alters
the cell’s normal cell cycle. As a result, in CML the cells start to divide
way too quickly and in CLL the cell’s don’t die when they should — and in both situations,
we’re left with way too many of these premature cells. So over time, premature leukocytes accumulate
in the bone marrow, until eventually they spill out into the blood. Now some of these guys settle down in organs
and tissues across the body, but others keep circulating in the blood. With a bunch of extra cells in the blood,
all the healthy cells get “crowded out”, and it’s tough for them to survive with
the extra competition for nutrients. This causes cytopenias, or a reduction in
the number of healthy blood cells, like anemia, which is a reduction of healthy red blood
cells, thrombocytopenia, a reduction of healthy platelets, and leukopenia, or a reduction
of healthy leukocytes. In chronic myeloid leukemia, the most common
cause is a chromosome translocation which results in a Philadelphia chromosome. And that’s where a portion of chromosome
9’s long arm switches with a portion of chromosome 22’s long arm — and we write
that as t(9;22) — t because it’s a translocation, and 9 and 22 because those are the chromosomes
that switch genetic information. This results in a modified chromosome 9 and
modified chromosome 22, and it’s the chromosome 22 that’s called the Philadelphia chromosome. So, in the Philadelphia chromosome, a chromosome
22 gene, which is the BCR gene, ends up sitting right next to a chromosome 9 gene, the ABL
gene. When they’re combined it forms a fusion
gene called BCR ABL, which codes for a protein also called BCR ABL, and that protein activates
enzymes called tyrosine kinases. Some of these tyrosine kinases are like on/off
switches for various cellular functions, including cell division. So when the BCR ABL fusion protein turns on
these tyrosine kinases, it forces myeloid cells to keep dividing quicker than they should,
which causes a buildup of the premature leukocytes in the bone marrow, that eventually spill
into the blood. The premature leukocytes then move to the
liver and spleen, causing swelling of those organs or “hepatosplenomegaly”. And because these CML cells divide quicker
than they should, there’s a high chance that further genetic mutations can happen! And if that happens, CML might progress and
accelerate into a more serious acute leukemia, which is called a blast crisis, because the
totally immature cells of acute leukemias are referred to as blasts. A lot of cases of these blast crises include
the formation of a trisomy on chromosome number 8, or the doubling of the Philadelphia chromosome. In chronic lymphocytic leukemia, the most
likely cause is also mutation in the cells’ chromosomes — we just don’t know which
particular mutation, or mutations. Whatever the case the result is that B cells
start to interfere with the pathways of B cell receptors, which should only be signalled
during infection to activate a few specific tyrosine kinases. Interference with Bruton’s tyrosine kinase,
for example, is probably what stops CLL cells from maturing fully, and it’s similar interference
with other tyrosine kinases that allows them to die slower than they divide, which is why
they build up. These premature cells always express particular
proteins on their surfaces including CD5, CD19, and CD23. The CD part stands for “cluster of differentiation”,
because these are common surface proteins which can be used to differentiate between
the lymphocytes. And despite CLL cells being B lymphocytes,
they express the CD5 protein, which is a lot more common in T lymphocytes. Anyway, these premature leukocytes build up
in the bone marrow and eventually spill into the blood, like in CML. Some of these cells then move to the lymphatic
system, where normal lymphocytes go, and although this does include the spleen, the lymph nodes
are prioritized. This causes swelling of the lymph nodes, or
“lymphadenopathy”. Then eventually, B cells in these nodes will
accumulate into distinct masses, or “lymphomas”, which is why mature CLL is sometimes called
small lymphocytic lymphoma. Further progression might take the form of
a Richter transformation, where those small, pretty harmless lymphomas collect into sizable
masses that damage the body. And, because B cells normally work in the
immune system, the reduced or adverse functioning of CLL cells might result in autoimmune hemolytic
anemia, where the cells attack the body’s own red blood cells and kill them off, or
hypogammaglobulinemia, where the cells don’t produce enough gamma globulins. Symptoms of both CML and CLL include fatigue,
because of anemia, easier bleeding, because of thrombocytopenia, and more frequent infection,
because of leukopenia. In CML the hepatosplenomegaly of CML often
causes a feeling of abdominal fullness, while the lymphadenopathy of CLL often causes mild,
but localized pain in the lymph nodes. The diagnosis of CML and CLL usually starts
with a blood smear, which shows a lot of premature leukocytes. In CML, there are an increased number of granulocytes
and monocytes and in CLL, there are often “smudge” cells on the blood smear — immature
B cells that have broken during the smear. For a conclusive diagnosis, genetic testing
can be done to look for the Philadelphia chromosome in CML and to look for chromosomal defects
in CLL. Treatment for CML always includes biological
therapy, with a tyrosine kinase inhibitor aimed at stopping cell division caused by
the BCR ABL protein. This is less effective for CLL though, as
there’s no specific target. Other options for both CML and CLL include
chemotherapy, stem cell transplants, or bone marrow transplants All right, as a quick recap… chronic leukemia
is a cancer of the leukocytes that includes both CML and CLL. In CML, a chromosomal translocation results
in a Philadelphia chromosome which codes for a protein called BCR ABL. As a result, myeloid leukocytes like granulocytes
and monocytes stop maturing and reproduce too quickly. These build up in the liver and spleen causing
hepatosplenomegaly. In CLL, a variety of chromosomal abnormalities
interfere with the pathways of B cell receptors. As a result, lymphoid leukocytes like B cells,
or B lymphocytes, stop maturing and die too slowly. They build up mainly in the lymph nodes causing
lymphadenopathy. Both cause a loss of normal blood cells, resulting
in things like anemia, thrombocytopenia, and leukopenia.