Hold your nerve; a new way to halt MPN progression

Written by William Foster

Edited by Judith Secklehner

On Monday the 15th of February the NHLI welcomed Dr Simón Méndez-Ferrer for a lunchtime seminar. Dr Méndez-Ferrer has recently moved from Madrid to Cambridge, where he has established a group in the Haematology department. Dr Méndez-Ferrer studies the multisystem regulation of the haematopoietic stem cell niche and his work has clinical implications for bone marrow transplantation procedures, as well as insight into specific forms of leukaemia. In Simón’s talk he discussed haematopoietic stem cell trafficking; paying attention to the importance of microenvironments; with focus on the importance of neural signal modulation within the bone marrow and how Mesenchymal Stem cells(MSCs) regulate inflammatory cell trafficking.

The focus of the journal club was on a paper published by the Méndez-Ferrer group in Nature in 2014. The paper is titled “Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms” and can be found at http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13383.html

Myeloproliferative neoplasms (MPNs) are a family of diseases characterised by the bone marrow overproducing one or more blood cell types. The disease manifests as mutations in the Haematopoietic stem cell (HSC) compartment.  The majority of MPN patients show a common mutation in Janus Kinase 2 (JAK2) in their HSCs. This mutation causes constitutive activation of the kinase, leading to haematopoietic cells becoming more sensitive to growth factors like thrombopoietin, which leads to over-proliferation.

Simón’s previous work showed that the HSC niche is controlled by nestin+ MSCs which are innervated by the sympathetic nervous system. This paper demonstrates that during MPN pathogenesis, the MSC/HSC cellular circuit is corrupted. In both human patients and mouse models nestin+ MSCs, sympathetic nerve fibres and their supporting Schwann cells were depleted. In pathological conditions, loss of stem cell populations can often be attributed to loss of their quiescence, leading to differentiation away from the stem cell phenotype. However in this work, MSC depletion was shown to be due to an increased rate of apoptosis. Through the use of multiplex ELISA assays, the group showed that IL-1β is upregulated by mutant HSCs, and this can sensitise the neural cells for apoptose. Time course experiments showed that MSC apoptosis occurs after the loss of innervating nerve fibres, and so the paper then goes on to show that if the nerve cells are protected, so are the MSCs.

Experiments in the second half of the paper aim to prevent the development of MPN pathology through the use of neuroprotective agents (4-methylcatechol) and β-3 adrenergic agonists (BRL37344). The use of β-3 adrenergic agonists supplement the MSCs which are not receiving stimulus from the sympathetic nervous system, and BRL37344 treatment prevented the neutrophilia and thrombocytosis seen in unchecked MPN disease. The paper also displays some impressive histological work, showing that use of BRL37344 prevents the build-up of fibroblastic and bone tissue deposits. In addition to initial prevention of disease manifestation, BRL37344 is presented as a therapeutic candidate, as it was demonstrated to reduce the proliferative phenotype and rescue bone marrow Schwann cells in mice with more advanced stages of thrombocytosis. Ultimately the root of MPN development lies with the mutant HSCs within the bone marrow, and therefore any therapeutic intervention should seek to reduce the number of mutant HSCs. The paper concludes with showing that early stage treatment can prevent mutant haematopoietic progenitor proliferation and that ultimately, MPN mice treated with BRL37344 have a significant decrease in leukaemic stem cells.

MPN progressFigure from Arranz et al (Nature, 2014)

During the journal club discussion, Simón discussed how he is in the process of setting up clinical trials and his desire to test additional (alternative) treatment to the current JAK2 inhibitors currently available for treating MPN. We discussed the benefits of combination therapies for MPN patients; that would be more specific and have less severe side effects. Finally Simón gave us some advice as young scientists: stay excited, come up with original concepts, don’t forget the big picture, and most importantly, don’t worry if some of your experiments don’t work!

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