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).
Just a quick question: you say that CML certainly doens’t have more than 20% of blasts in circulation, but in class my teacher mentioned that in the blastic phase of CML 20% or more blasts can be found. Is this due to the fact that at this stage CML is so advanced that the body overproduces many blasts to try to replace the abnormal myeloid mature cells?
Thanks in advance!
Good question. In regular “chronic phase” CML, the blast count is low. However, in blast crisis (or blast phase) CML, the blast count is 20% or more, just like an acute leukemia. This is because the malignant cells acquire new genetic abnormalities as the disease progresses. One of these abnormalities happens in progenitor cells: they acquire the ability to self-renew (like stem cells)! They also acquire a differentiation block (meaning that they no longer mature out into regular neutrophils – they stay in the progenitor (blast) phase. This is a very ominous sign.
So, does that mean that as the disease progresses the number of mature cells will decrease (as opposed to what happens with the number of blasts)?
Overall, the tendency as CML progresses is for the white count to continue to rise. If the patient enters blast crisis, the percentage of mature cells would decrease (they’d account for 80% or less of the total number of white cells) – but the count is usually pretty high at that point – so the absolute number would most likely still be going up. It’s best to think of the number of mature cells increasing as the disease progresses, because that’s usually what happens. There’s another phase called “acute phase” in which the white count soars despite all efforts to keep it in check.
Referring to what you said earlier, would it then be correct to consider that part of the progenitor cells that acquires the capicity to self-renew will actually NOT acquire the differentiation block, eventually transforming into mature cells, and that another part of the progenitor cells will acquire both of the abnormalities, which would lead to blasts? I think this would explain the increase in the numbers of both mature and immature cells, but my line of thought could be wrong..
Hmmm…I don’t know the answer to that one. I think that could be true; or it could be that you’re still seeing the effects of the “old” group of progenitor cells that still shows maturation. The “new” progenitor cells may very well all have the differentiation block. Even with a differentiation block, it seems that cells can “escape” from time to time (for example, in AML-M3, there is a block at the promyelocyte stage – and you see mostly promyelocytes – but there are always a few more mature neutrophilic cells around too, for some reason).
What you said in your answer would make sense too. Either way, it seems that the pathway of progression from chronic phase to blast crisis is still poorly understood, but some articles I found argue that the BCR-ABL fusion gene may trigger secondary events that cause the differentiation block.
Thanks so much for your input! It was really helpful to clear some aspects about CML.
1)Can we call the mature appearing neutrophils in CML as malignant?
2) Why there is Low Lap score in CML
Thanks
Yes – the mature appearing neutrophils in CML are part of the malignant population! The LAP is low because the neutrophils in CML are malignant – and they don’t produce LAP like normal neutrophils.
So, say in a particular case that the patient’s blast (7%) and promyelocyte (10%) counts outnumber the myelocyte (5%) and metamyelocyte (3%) counts on the differential, but he is not in blast crisis and isn’t showing signs of progression to acute phase. What is this called?
If you’re sure it’s CML, I’d say that he’s heading towards accelerated phase (in which the blast count is 10% or more). From your numbers, though, it doesn’t look like CML. Is there a basophilia or a Philadelphia chromosome?
I’m not 100% sure it’s CML, but basophilia is present. No cytogenetic information is available yet, as this is the initial visit information. Patient presents with splenomegaly and anemia.
Also, there is evidence of weight loss and fatigue. Patient feels full only after eating a small amount of food. Is it possible that he is in accelerated phase even though his blast count is only 7%?