The following abstract involved the work of Dr Ron Hoffman, the principle investigator (PI), senior member of the MPN group at Mt Sinai Hospital in New York City as well as the PI of the MPN-RC. Xiaoli Wang, Phd, performed all of the lab work. Dr John Mascarenhas was my point of contact for this article and a contributor to the study.
Commentary by Dr John Mascarenhas
This paper is important because it shows for the first time that interrupting the TPO-MPL axis has potential therapeutic implications for the treatment of MPNs. TPO is the signaling molecule that engages its cognate receptor (MPL) on the surface of hematopoietic stem cells and megakaryocytes and induces changes in their function and proliferation. In MPNs it has been shown previously that TP is elevated and MPL is downregulated. LCP4 antagonized the MPL receptor and inhibits TPO from binding. In these experiments conducted here, LCP4 led to selective eradication of the malignant MPN hematopoietic stem cells and not normal cells. Ultimately, the testing of a TPO antagonist in patients with MF is warranted based on this compelling preclinical study. This would be a very exciting treatment approach that could lead to disease modifying effects.
MPN Clinical Trial, Phase 1
Additionally, I would like to highlight for your readership a very exciting ongoing MPD-RC trial of RG7388 in patients with JAk2V617F positive ET or PV. This is an oral MDM2 inhibitor that has shown promise in preclinical laboratory work by Dr Hoffman. MDM2 levels are elevated in patients with JAK2V617F –positive MPNs and this protein negatively regulates TP53 (a crucial tumor suppressor oncoprotein). RG7388 binds MDM2 and disengages it from TP53 which then allows this protein to activate a pathway that signals the malignant cell to die. This was very effective in primary MPN cells and has already provided a signal of clinical activity early on in the trial. This phase I trial is already open at Mount Sinai, Wake Forest, and Georgetown. Anyone interested in learning more can read about it here https://clinicaltrials.gov/ct2/show/NCT02407080?term=RG7388&rank=1 or contact me through email: email@example.com
Treatment of MF CD34+ cells with a thrombopoietin receptor antagonist selectively depletes MF hematopoietic stem/progenitor cells.
Agents which target the thrombopoietin receptor represent potentially new approaches for treatment of MF patients.
Recently, interactions between thrombopoietin (TPO) and its receptor (MPL) have been shown to play a role in the development and progression of myeloproliferative neoplasms (MPN) including myelofibrosis (MF). These observations have led to the development of strategies to disrupt the association of TPO with its receptor as a means of targeting MF hematopietic stem cells (HSCs) and progenitor cells (HPC). In this report, we show that although both splenic and peripheral blood (PB) MF CD34+ cells expressed lower levels of MPL than normal CD34+ cells, TPO promoted the proliferation of MF CD34+ cells and HPCs in a dose-dependent fashion. Furthermore, treatment of MF but not normal CD34+ cells with a synthesized MPL antagonist, LCP4, decreased the number of CD34+Lin– cells and all classes of assayable HPCs (CFU-Mk, CFU-GM, BFU-E/CFU-E, and CFU-GEMM) irrespective of their mutational status. In addition, LCP4 treatment resulted in a depletion of the number of MF HPCs that were JAK2V617F+. Moreover, the degree of human cell chimerism and the proportion of malignant donor cells were significantly reduced in immunodeficient mice transplanted with MF CD34+cell grafts treated with LCP4. These effects of LCP4 on MF HSCs/HPCs were associated with inhibition of JAK-STAT activity, leading to the induction of apoptosis. These findings demonstrate that such specific anti-cytokine receptor antagonists represent a new class of drugs that are capable of targeting MF HSCs.