Riddhi Rane

Introduction: Myeloproliferative Neoplasms (MPNs) are a group of clonal hematopoietic disorders that are characterized by an overproduction of hematopoietic cells.¹ Disease complications of MPNs include thrombosis, leukemic transformation, and fibrotic transformation.^2,3 The exact cause of MPNs is currently unknown. However, certain driver mutations are associated with a higher risk of developing an MPN and its subsequent complications. The phenotypic drivers of the disease include mutations coding for JAK2 tyrosine kinase, calreticulin (CALR) and MPL, a thrombopoietin receptor.^4,5 Mutations in these proteins result in constitutive activation of JAK2 as well as its downstream pathways, which normally function to control cell proliferation and metabolism. The overactivation of downstream pathways causes much of the disease’s pathological progression and therefore, should be further investigated as adjunctive potential targets for therapeutic effects in MPNs. Methods: Many of these studies utilized either mouse MPN cells, or induced MPN in mice via Tamoxifen. Subsequently, the mouse MPN cells or Tamoxifen induced mice were exposed to a JAK2 inhibitor, Ruxolitinib, and pathological phenotypes such as inflammatory responses and metabolic changes were measured. ^6,7,8 Results: Stivala et. al saw that despite JAK2 inhibition via Ruxolitinib, downstream activation of MEK/ERK signaling pathways persisted. This indicated that a cell-extrinsic factor, in this case PDGFα, bypassed JAK2 inhibition and activated MEK/ERK signaling to maintain the pathogenesis of MPNs. The study therefore, suggests that maximal therapeutic capability can be obtained by not only inhibiting JAK2 as the driver mutation, but also by inhibiting its downstream signaling pathways that may be independent of JAK2 activation.⁶ Rao et. al saw that MPN mice showed heightened metabolic processes such as glycolysis. These mice presented with adipose atrophy and hypoglycemia that could only be corrected via JAK2 inhibition. They concluded that targeting the rate limiting step of these metabolic pathways could help decrease disease burden.⁷ Lastly, Kleppe, et. al determined that MPN patients are often found with elevated TNFα / NF-kB inflammatory pathway activation. Administration of JQ1, an inflammatory pathway inhibitor in conjunction with JAK2 inhibitor resulted in higher malignant cell mortality as compared to JAK2 inhibition alone.⁸ Conclusion: Studies have found that inhibition of the phenotypic drivers of MPNs may not be enough to reduce the disease burden and limit the symptoms of MPNs. Targeting downstream effects of the driver mutations show promising results for added symptomatic relief and decreased viability of malignant cells and should be further investigated as potential therapeutic targets in myeloproliferative neoplasms.

1. Nangalia, J. and Green, A., 2017. Myeloproliferative neoplasms: from origins to outcomes. Blood, 130(23), pp.2475-2483.
2. Tefferi, A. and Pardanani, A., 2015. Myeloproliferative Neoplasms. JAMA Oncology, 1(1), p.97.
3. Tefferi, A., 2015. Myeloproliferative neoplasms: A decade of discoveries and treatment advances. American Journal of Hematology, 91(1), pp.50-58.
4. Nangalia, J., Nice, F., Wedge, D., Godfrey, A., Grinfeld, J., Thakker, C., Massie, C., Baxter, J., Sewell, D., Silber, Y., Campbell, P. and Green, A., 2015. DNMT3A mutations occur early or late in patients with myeloproliferative neoplasms and mutation order influences phenotype. Haematologica, 100(11), pp.e438-e442.
5. Barbui, T., Tefferi, A., Vannucchi, A., Passamonti, F., Silver, R., Hoffman, R., Verstovsek, S., Mesa, R., Kiladjian, J., Hehlmann, R., Reiter, A., Cervantes, F., Harrison, C., Mc Mullin, M., Hasselbalch, H., Koschmieder, S., Marchetti, M., Bacigalupo, A., Finazzi, G., Kroeger, N., Griesshammer, M., Birgegard, G. and Barosi, G., 2018. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia, 32(5), pp.1057-1069.
6. Stivala S, Codilupi T, Brkic S, et al. Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms. J Clin Invest. 2019;129(4):1596-1611. Published 2019 Mar 4. doi:10.1172/JCI98785
7. Rao TN, Hansen N, Hilfiker J, et al. JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms. Blood. 2019;134(21):1832-1846. doi:10.1182/blood.2019000162
8. Kleppe M, Koche R, Zou L, et al. Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms. Cancer Cell. 2018;33(4):785-787. doi:10.1016/j.ccell.2018.03.024