Question about Polycythemia Vera

[VTBuc]

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Hi all, I'm a bit confused about this disease. So I understand it's a result of a mutation of JAK2 which causes constitutional de-activation and removes the need for EPO stimulation. Rubin's Pathology says that this de-coupling of stimulus/response occurs at the GFU-E stage of erythrocyte development(which, from what I understand is past the point of no return for differentiating into a specific cell type). So my confusion comes in understanding why with Polycythemia Vera patients have high platelets and neutrophils. If someone could enlighten me or direct me towards a source, I'd greatly appreciate it. Thanks!

 

[shadowfox87]

In simplest terms from Robbins, the JAK2 point mutation is responsible for regulation of hematopoietic growth receptors, ONE of which is the EPO receptor. So even though EPO levels are low, the EPO receptor is still being stimulated. It's a constitutive mutation, so it basically signals the hematopoietic growth receptors to be always ON. It's not only affecting EPO like I said, but also affects other growth receptors, including that of granulocytes and thrombocytes, hence you get a panmyelosis. However, all the symptoms are really explained by the increased RBC.

You should also know that unlike in CML, that also has a panmyelosis, the JAK2 mutation signals are weaker than the BCR-ABL signals (even though both JAK2 and BCR-ABL are TRKs), hence in CML you get MORE marrow hypercellularity, splenomegaly, and leukocytosis.

Rubin's is probably right, though I've never read it, but you're only reading about the erythrocytes, there's also other receptors affected of the other cell types (granulocytes and platelets).

 

[VTBuc]

Thank you for your quick response. However, it was my understanding that PV represents a clonal expansion of a mutated CFU-E cell. So regardless of whether or not JAK2 is involved in other growth factors, wouldn't the pathologic process(clonal expansion) be limited to the erythrocyte lineage?

 

[shadowfox87]

Thank you for your quick response. However, it was my understanding that PV represents a clonal expansion of a mutated CFU-E cell. So regardless of whether or not JAK2 is involved in other growth factors, wouldn't the pathologic process(clonal expansion) be limited to the erythrocyte lineage?

I have no idea where you're getting that mutation from, maybe from research papers, but from all the pathology books I've read (Robbins, BRS, Pathoma, Goljans), it states that 95% of the time, JAK2 mutation is THE cause of PCV.

You're thinking of a different kind of polycythemia. Normally, polycythemia refers to increased erythrocytes, but there is absolute and relative kinds. PCV is a subcategory of the absolute type, where more than just the erythrocyte lineage is involved.

 

[Gut Shot]

Thank you for your quick response. However, it was my understanding that PV represents a clonal expansion of a mutated CFU-E cell. So regardless of whether or not JAK2 is involved in other growth factors, wouldn't the pathologic process(clonal expansion) be limited to the erythrocyte lineage?

1. You have probably learned the standard tree version of hematopoiesis. This model is simple to teach and learn but reality is much more complicated (and still being worked out).
2. The bone marrow is not a homogenous compartment, but a series of innumerable microenvironments where the blood components mature via an intricate control system. Dysregulation of one cell line may absolutely cause ancillary effects in the rest of the system.
3. The most common JAK2 mutation is most closely associated with polycythemia vera, but also occurs in moderately lower frequency in primary myelofibrosis and essential thrombocythemia. How one mutation causes three diseases is not yet known. Gene dosage may play an important role (see PubMed).

 

[shadowfox87]

If you really want to go in-depth, you'd have to google the JAK2/STAT pathway which is pretty complex and overlaps with other pathways as well. The single point mutation in JAK2 is what they wrote in the book to simplify it for others. To get 3 different diseases obviously involves more criteria than just that mutation. The other two diseases, essential thrombocytopenia and primary myelofibrosis can also be caused by MPL point mutations, while PCV can ONLY be caused by JAK2 mutation.

 

[Gut Shot]

The single point mutation in JAK2 is what they wrote in the book to simplify it for others.

The most common JAK2 mutation is V617F, which is what you are referring to. There are others involving exon 12, and more will almost certainly emerge over time.

The other two diseases, essential thrombocythemia and primary myelofibrosis can also be caused by MPL point mutations, while PV can ONLY be caused by JAK2 mutation.

Fixed that for you.

 

[shadowfox87]

Fixed that for you.

Haha yea thx. Though, in Robbins, they always use PCV not PV, not a big deal, just convention.

 

[VTBuc]

Thank you so much for your response! That helped tremendously.

 

[Gut Shot]

Haha yea thx. Though, in Robbins, they always use PCV not PV, not a big deal, just convention.

I haven't seen my copy of Robbins in a few years, so I'll take your word for it. The WHO classification uses PV. Hemepath is great if you like to nitpick.