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Chronic leukemia



Hematological system


Heme synthesis disorders
Coagulation disorders
Platelet disorders
Mixed platelet and coagulation disorders
Thrombosis syndromes (hypercoagulability)
Leukemoid reaction
Dysplastic and proliferative disorders
Plasma cell dyscrasias
Hematological system pathology review

Chronic leukemia


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High Yield Notes
8 pages

Chronic leukemia

17 flashcards

USMLE® Step 1 style questions USMLE

5 questions

A 60-year-old man comes to the office because of progressive weakness and a dragging sensation in the abdomen for the past 3 months. The patient is a retired farmer. Past medical history is noncontributory. He does not smoke or use illicit drugs. Temperature is 37.0°C (98.6°F), pulse is 96/min, respirations are 20/min, and blood pressure is 125/80 mmHg. Physical examination shows mucosal pallor, petechiae on the lower extremities, and splenomegaly crossing the midline. Laboratory results are as follows:  

 Laboratory value  Result 
 Complete blood count 
 Hemoglobin   9.3 g/dL 
 Platelets   70,000/mm3 
 Leukocytes   6,000/mm3 
Peripheral blood smear is shown:

Reproduced from:Wikimedia Commons 

Which of the following genes is most likely to be mutated in this patient?  

External References

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 multipotent -- 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, which is a constitutively active tyrosine kinase, meaning that BCR ABL is like an “on/off” switch stuck in the “on” position.

Since BCR ABL helps control various cellular functions like cell division, having it always “on” 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!

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