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


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


of JAK/STAT pathway16

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


on BCL-2–family proteins14

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


of malignant stem cells and activation of myofibroblasts4,6

An illustration representing worsening bone marrow fibrosis and disease progression


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

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.


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  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
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  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
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