Multiple pathways drive myelofibrosis progression1

Pathways include JAK/STAT, BCL-2 family, epigenetic regulators, PI3K, and RAF/MEK/ERK (MAPK)1,2

  • Targeting the downstream signaling may still permit malignant stem cells to evade apoptosis and the disease to progress2,3
  • Additional pathways allow the continued survival of malignant clones that drive disease progression3,4

Pathways involved in myelofibrosis

An illustration of a myelofibrosis stem cell and the pathways that lead to myelofibrosis progression

PATHWAYS INVOLVED IN MYELOFIBROSIS

Survival and proliferation of malignant stem cells leads to aberrant megakaryocytes, increased cytokine production, myofibroblast activation, and progressive bone marrow fibrosis1,3-10

Survival and proliferation of malignant stem cells leads to aberrant megakaryocytes, increased cytokine production, myofibroblast activation, and progressive bone marrow fibrosis4-7,11,12

Anti-apoptotic members of the BCL-2 family may play a role in the progression of myelofibrosis13,14

Myelofibrosis cells have been shown to be primarily dependent on BCL-XL and MCL-1 anti-apoptotic proteins for survival, leading to apoptosis resistance13-15

BCL-XL and MCL-1, as well as other anti-apoptotic BCL-2–family proteins, remain active and may contribute to MF progression6,14,15

An illustration of the activation of JAK/STAT pathway

Activation

of JAK/STAT pathway16

An illustration of the overexpression of BCL-2-family proteins

DEPENDENCE

on BCL-2–family proteins14

An illustration of the survival of malignant stem cells and activation of myofibroblasts

Survival

of malignant stem cells and activation of myofibroblasts4,6

An illustration representing worsening bone marrow fibrosis and disease progression

Worsening

bone marrow fibrosis and disease progression3,12

By evading apoptosis, malignant stem cells continue to proliferate, leading to worsening bone marrow fibrosis and the progression of the underlying disease14,15

Greater understanding of these pathways may identify opportunities that address both symptoms and underlying progression17,18

Therapeutic Goals

AKT=protein kinase B; BCL-2=B-cell lymphoma 2; BCL-XL=B-cell lymphoma-extra large; ERK=extracellular-signal–regulated kinase; JAK/STAT=Janus kinase signal transducer and activator of transcription; MAPK=mitogen-activated protein kinase; MCL-1=myeloid cell leukemia-1; MEK=MAPK/ERK kinase; MF=myelofibrosis; mTOR=mammalian target of rapamycin; PI3K=phosphoinositide 3-kinase; RAF=rapidly accelerated fibrosarcoma.

References:

  1. Pettit K, Odenike O. Novel therapies for myelofibrosis. Curr Hematol Malig Rep. 2017;12(6):611-624. doi:10.1007/s11899-017-0403-0
  2. Schieber M, Crispino JD, Stein B. Myelofibrosis in 2019: moving beyond JAK2 inhibition. Blood Cancer J. 2019;9(9):74. doi:10.1038/s41408-019-0236-2
  3. Santos FPS, Verstovsek S. Therapy with JAK2 inhibitors for myeloproliferative neoplasms. Hematol Oncol Clin North Am. 2012;26(5):1083-1099. doi:10.1016/j.hoc.2012.07.008
  4. Gleitz HFE, Pritchard JE, Kramann R, Schneider RK. Fibrosis driving myofibroblast precursors in MPN and new therapeutic pathways. HemaSphere. 2019;3(S2):142-145. doi:10.1097/HS9.0000000000000216
  5. Ishida S, Akiyama H, Umezawa Y, et al. Mechanisms for mTORC1 activation and synergistic induction of apoptosis by ruxolitinib and BH3 mimetics or autophagy inhibitors in JAK2-V617F-expressing leukemic cells including newly established PVTL-2. Oncotarget. 2018;9(42):26834-26851. doi:10.18632/oncotarget.25515
  6. Gozgit JM, Bebernitz G, Patil P, et al. Effects of the JAK2 inhibitor, AZ960, on Pim/BAD/BCL-xL survival signaling in the human JAK2 V617F cell line SET-2. J Biol Chem. 2008;283(47):32334-32343. doi:10.1074/jbc.M803813200
  7. Tremblay D, Mascarenhas J. Next generation therapeutics for the treatment of myelofibrosis. Cells. 2021;10(5):1034. doi:10.3390/cells10051034
  8. Feng Y, Chen X, Cassady K, et al. The role of mTOR inhibitors in hematologic disease: from bench to bedside. Front Oncol. 2021;10:611690. doi:10.3389/fonc.2020.611690
  9. Meyer SC, Levine RL. Molecular pathways: molecular basis for sensitivity and resistance to JAK kinase inhibitors. Clin Cancer Res. 2014;20(8):2051-2059. doi:10.1158/1078-0432.CCR-13-0279
  10. Moens U, Kostenko S, Sveinbjørnsson B. The role of mitigen-activated protein kinase-activated protein kinases (MAPKAPKs) in inflammation. Genes. 2013;4(2):101-133. doi:10.3390/genes4020101
  11. Yang Q, Crispino JD, Wen QJ. Kinase signaling and targeted therapy for primary myelofibrosis. Exp Hematol. 2017;48:32-38. doi:10.1016/j.exphem.2016.12.007
  12. Agarwal A, Morrone K, Bartenstein M, Zhao ZJ, Verma A, Goel S. Bone marrow fibrosis in primary myelofibrosis: pathogenic mechanisms and the role of TGF-β. Stem Cell Investig. 2016;3(5):1-10. doi:10.3978/j.issn.2306-9759.2016.02.03
  13. Petiti J, Lo Iacono M, Rosso V, et al. Bcl-xL represents a therapeutic target in Philadelphia negative myeloproliferative neoplasms. J Cell Mol Med. 2020;24(18):10978-10986. doi:10.1111/jcmm.15730
  14. Tognon R, Gasparotto EPL, Neves RP, et al. Deregulation of apoptosis-related genes is associated with PRV1 overexpression and JAK2 V617F allele burden in essential thrombocythemia and myelofibrosis. J Hematol Onc. 2012;5(2):1-11. doi:10.1186/1756-8722-5-2
  15. Rubert J, Qian Z, Andraos R, Guthy DA, Radimerski T. Bim and Mcl-1 exert key roles in regulating JAK2V617F cell survival. BMC Cancer. 2011;11:24. doi:10.1186/1471-2407-11-24
  16. Mughal TI, Vaddi K, Sarlis NJ, Verstovsek S. Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes. Int J Gen Med. 2014;7:89-101. doi:10.2147/IJGM.S51800
  17. Harrison CN, McLornan DP. Current treatment algorithm for the management of patients with myelofibrosis, JAK inhibitors, and beyond. Hematology Am Soc Hematol Educ Program. 2017;(1):489-497. doi:10.1182/asheducation-2017.1.489
  18. Kramann R, Schneider RK. The identification of fibrosis-driving myofibroblast precursors reveals new therapeutic avenues in myelofibrosis. Blood. 2018;131(19):2111-2119. doi:10.1182/blood-2018-02-834820