Q. If the chronic leukemias have lots of mature cells, and the acute leukemias have immature cells, then how come chronic myeloid leukemia has lots of immature cells? Seems like it belongs in the acute leukemia category!

A. I think the best way to look at it is to oversimplify it a little, to get at the basics, and then put in a little detail.

The oversimplified version is this: Acute leukemias are composed of immature cells (usually blasts), whereas chronic leukemias are composed of mature cells (mostly the ones you normally see in peripheral blood).

The problem with that definition is that it doesn’t quite cover every chronic and acute leukemia. For example, AML-M2 is an acute leukemia that has at least 20% myeloblasts – but there are also a fair number of maturing neutrophils too (promyelocytes, myelocytes, metamyelocytes, and segmented neutrophils). So that doesn’t quite fit. The important thing in this AML, though, is that it does have at least 20% blasts. So you have to call it AML, even though it doesn’t quite “fit” our nice little definition.

Another example that doesn’t quite fit our neat little definition, as you noted, is CML. In CML, most of the cells are pretty mature (segmented neutrophils, metamyelocytes)…but there are some less mature ones too (myelocytes, promyelocytes). The important thing in CML is that there really aren’t very many blasts around at all; certainly not 20% or more like you’d see in AML. So even though it doesn’t quite fit, we put it into the chronic category (and it certainly acts a lot more like a chronic leukemia than an acute one!).

The underlying reason you see all these mature (and maturing) cells in CML (and in the other myeloproliferative disorders) – rather than a bunch of blasts – is that the problem has to do with a mutated, constitutively activated growth receptor gene that occurs in a stem cell. This mutated gene produces a growth receptor that is permanently in the “on” position, which means that growth and proliferation signals are constantly being sent to the nucleus. So the cells are dividing and proliferating even when they shouldn’t be.

These mutated tyrosine kinases don’t impair differentiation (or maturation), though, so you get uncontrolled growth of stem cells, and these bad stem cells are able to mature and progress through the normal stages of development! This is in contrast to many other leukemias, where there is increased proliferation, but the cells are “stuck” at a certain stage of maturation (like the malignant cells in promyelocytic leukemia, which remain stuck at the promyelocyte stage).