Important Pathways and Biomarkers in Myeloproliferative Neoplasms
Expert hematologist-oncologists share insight on the pathways driving myeloproliferative neoplasms and biomarkers that may be targeted with novel therapy.
Transcript:
Rami S. Komrokji, MD: Having said that, it's important to shift gears and focus on the molecular aspects of the disease. Pankit, if you can walk us through the Janus kinase pathway, the JAK/STAT pathway because the discovery there was pivotal, this is a pathway that's overactivated in most of those patients with those diseases. Can you walk us through the role of the JAK/STAT pathway?
Pankit Vachhani, MD: Absolutely. Thank you, Dr Komrojki. The JAK/STAT signally pathway which is hyperactivated in the MPNs, this is a complicated and interconnected pathway which brings together a wide variety of proteins in the cellular processes. Now, simply put, there are 3 different players in the JAK/STAT pathway, the first one being a receptor that binds to a ligand from outside, let's say the extracellular ligand. And the second component is the JAK kinases, and there are 4 main JAK proteins that we know of. And then there's the third player in this JAK/STAT pathway which is the STAT proteins, and there are about 7 STAT proteins. At a very simplistic level, what the JAK/STAT pathway does is that it allows the transformation and the carry forward of the message from the ligands from outside of the cell to the nucleus of the cell which then allows for the activation of genes through the process of transcription. This is a complicated play and there is receptor dimerization, JAK and STAT get phosphorylated, the STATs go into the nucleus and then eventually lead to the transcription of a variety of genes. What we know is that this pathway is constitutively overactivated in MPNs across the board and this leads to then downstream effects, for example, there are alterations in the immune function, more cytokines are produced and released extracellularly, this plays an important role in cell division, cell death, as well as neoplastic evolution down the line. JAK/STAT pathway is important and plays a very central role in the normal and abnormal hematopoiesis. We think of JAK/STAT, one of those genes in the JAK/STAT pathway, for example, is the JAK2 gene, and mutations of JAK2 were first described in 2005. For example, the JAK2 V617F mutation, the classic mutation which is seen in PV, ET, and MF, was first described then. But we also know that JAK2 Exon12 mutations have been in polycythemia vera, either of these mutations and some of the other ones which we'll just talk about, all of them lead to an overactivation of JAK/STAT pathways. Dr Komrojki, there are these other mutations in other pathways which are also central to MPNs and we are discovering more and more about the role of these pathways, both from a diagnostic perspective, but also a therapeutic perspective, for example, the IRAK pathway, the MPL genes, the CSF3R, FLT3, CLR, can you tell us a little bit more about these?
Rami S. Komrokji, MD: Absolutely. First, thank you for the overview of the JAK/STAT pathway because I think it's pivotal. I was taught to emphasize also that the pathway is activated either by mutations or just by the cytokine excess and ligand activation, which clinically or practically takes us to the point that the JAK2 inhibitors would work in the absence of the JAK2 mutations because as a segue for your question as well, some of those mutations will activate the pathway as well. Obviously, the JAK V617F was the first one we found, the Exon12 particularly in P. vera, but now know that there are other mutations, this is a calcium channel regular endoplasmic, but when it's mutant, it's also activated in the MPL receptor and leads to overactivation. We know that the mutation occurs across the 3 common myeloproliferative diseases, or at least the MF and ET commonly, very rarely in PV. In myelofibrosis and ET, probably one-third of the patients will have the mutation, tends, in general, to be associated with a better outcome and less thrombotic events. Obviously, it's becoming an interest that this could be an immune target in the future for many proposed antibody-based or vaccine therapies actually. We know the MPL is present in a small subset of patients, sometimes those could be younger, some of those are inherited, but it's also obviously an activation of the JAK/STAT pathway through the TPO receptor. We've learned also that other pathways, inflammatory pathways are important, like the mitosome and the IRAK is a downstream of that. Some of the newer JAK2 inhibitors inhibit that, the inflammatory pathways, there is some redundancy on those other pathways that are activated. CSF3R is a uniquely enriched mutation seen in patients with chronic neutrophilic leukemia that leads to overactivation of the JAK/STAT through the GCSF pathway. We know much more about those mutations, again, we have the classical, what we call the phenotype driver mutations, the JAK2, or the MPL, but there are other mutations. We also recommend usually checking the whole area of the myeloid gene panels because there are other mutations, not the phenotype driver, but there are mutations that tell us about the disease origin, for example, the CHIP-related mutations that are thought to be disease-initiating, and there are mutations that tell us about the progression of the disease like ASXL1, SLSS2, IDH1, IDH2, etc.
Transcript edited for clarity.
