Texas MPN Workshop 2021 | Thrombopoietin receptor MPL: a potential therapeutic target for MPNs

First, I want to say that my questioner does not know that this is something that we’re working on very heavily. And what do we know about targeting the thrombopoietin receptor? Well, stem cells are absolutely fascinating cells, and some of the fascination comes from the fact that they only have one hematopoietic growth factor receptor that they express and that’s the thrombopoietin receptor MPL. And a second fascinating thing about stem cells is that they also express the von Willebrand protein. And finally, for a stem cell to stay quiescent in its bone marrow niche, it needs megakaryocytes and thrombopoietin, which is provided by osteoblasts. And this anchors the stem cells along with other adhesive proteins in their osteoblasts niche. And then, they are adjacent megakaryocytes, which secrete TGF-beta and CXCL4. And these tend to keep the stem cell out of cell cycle.

Now, the stem cells will periodically go into cell cycle for the purpose of actually not only multiplying but also cleaning up any DNA errors of DNA metabolism that have occurred while they’re in the quiescent state. So, what nature has worked out and it’s known best in murine stem cells is that the hemato-, pluripotent hematopoietic stem cell gives rise to megakaryocytic stem cells. And one proof of that is a number of women with so-called triple-negative mutations with ET actually have expression of the JAK2 V617F mutation only in their platelets, and there’s no other way that could happen without the stem cell. Stem cells also make megakaryocyte erythroid precursors, and we do see that type of leukemia in polycythemia vera. And finally, they make a common stem cell, which makes megakaryocytes, erythroid cells and myeloid cells.

In addition to the so-called default pathway, that does the same thing. So, these cells are not only complex, but they have an Achilles’ heel, and that is the thrombopoietin receptor. And a number of years ago, we took mice with a transgenic mice expression JAK2 V617F that have a very nice model of the natural history of polycythemia vera pioneered by my colleague, Joe Zhao, at the University of Oklahoma. And we purposely knocked out the thrombopoietin receptor, and that abrogated the polycythemia vera phenotype. Now, mice are not humans. They can live without the thrombopoietin receptor. They still make about 20% of their platelets without it. But what happens if you knock out thrombopoietin and you still have a thrombopoietin receptor with an active JAK2 V617F as its tyrosine kinase? When you do that in these transgenic mice, you again abrogate the polycythemia vera phenotype so that this gives rise to the concept that these diseases are hormone-dependent.

What’s interesting here is if you have a mouse with a JAK2 V617F as a heterozygote, and so you have one copy of MPL, one copy of JAK2 that’s abnormal, this does not restore the polycythemia vera phenotype in this mouse model. If you have one, if you’ve lost a thrombopoietin gene, but you still have one active thrombopoietin gene, then you can restore the polycythemia vera. So, the bottom line here, and this has been seen in the test tube with erythropoietin, that heterozygous and possibly homozygous individuals with JAK2 V617F, if thy, it’s true in mice, if they’re deprived of the hormone, either erythropoietin for red cells or thrombopoietin for all the other cells, then you can abrogate the abnormal behavior of the stem cell.

So, I think this is a real place that one can look, and there are ways to possibly do this by silencing the thrombopoietin production or antagonizing it. And they’re people, obviously, looking into this because this is a non-myelotoxic way of controlling a disease in which patients are ordinarily with sufficient phlebotomy therapy to lead useful lives.