Q. I have a quick question on the cell of origin in leukemia. In our pharmacology class, we went through a section on cancer. There was a slide that said leukemia is a tumor of hematopoietic stem cells. But leukemia involves more than just hematopoietic stem cells, right? I think I remember from our pathology class that leukemia can also involve cells downstream of hematopoietic stem cells.

A. You’re absolutely right! Which means you really understood the heme part of our pathology class! Just to back up a bit: all leukemias arise from hematopoietic cells (either myeloid or lymphoid cells). But not all leukemias arise in hematopoietic stem cells. Let’s take a look.

Some leukemias arise in stem cells.
All of the chronic myeloproliferative disorders, for example, originate in stem cells. As a result, when you look in the blood and bone marrow, you see a proliferation of all different kinds of myeloid cells (red cells, neutrophils, and megakaryocytes) at all stages of maturation (neutrophils, myelocytes, metamyelocytes, etc.). In most of the chronic myeloproliferative disorders, a particular myeloid cell line dominates (in chronic myeloid leukemia (CML), for example, most of the malignant cells are neutrophils and precursors) – but because of the stem cell origin, there are other malignant myeloid cells present as well.

Here’s a cool thing. You’d think that the stem cell of origin in these chronic myeloproliferative disorders would be a myeloid stem cell, right? I mean, these disorders are composed of all kinds of myeloid cells – so the origin should be a myeloid stem cell. It turns out that the stem cell involved is actually a very young stem cell – it hasn’t even decided whether it wants to be myeloid or lymphoid! We know this because the characteristic genetic abnormality (for example, the Philadelphia chromosome in CML) is also present in lymphocytes. That explains why when CML evolves into blast crisis, the blasts may be either myeloid or lymphoid

Other leukemias arise in non-stem cells that belong to a specific cell lineage.
Acute promonocytic leukemia, for example, originates in a promonocyte (a stage of development between monoblast and monocyte). This means that when you look at the blood and bone marrow, you see mostly promonocytes (the cells in the image above with the lovely tissue-paper-like nuclei). Cells of other myeloid cell lineages (like red cells or neutrophils) are not present. These types of leukemias are a lot more straightforward.

Heme mistakes like this are common!
This kind of mis-statement (“all leukemias arise from stem cells”) happens a lot when people talk about hematopoietic diseases. Even the names of diseases are often stated incorrectly (e.g., “acute lymphoid leukemia” or “acute lymphocytic leukemia” instead of “acute lymphoblastic leukemia”). Heme is an area that many people shy away from, for some reason. I love it and find it really straightforward, but depending on how it’s taught, it can seem really confusing.

If you’re struggling with heme, there are tons of heme-related posts here on Pathology Student. You might also find my Complete Hematopathology Guide useful; it covers all the main hemepath stuff in a straightforward, no-BS way.