There may be more to MF
than the JAK‑STAT pathway.1,2

Although JAK inhibition has been accepted as the standard of care for years, more discoveries continue to be made about the heterogeneity of myelofibrosis (MF).3,4 Understanding the complex needs of patients—especially those with primary MF and the cytopenic phenotype—may require looking beyond the JAK-STAT pathway.4

JAK=janus kinase; STAT=signal transducer and activator of transcription.
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There may be more to MF
than the JAK‑STAT pathway.1,2

Although JAK inhibition has been accepted as the standard of care for years, more discoveries continue to be made about the heterogeneity of myelofibrosis (MF).3,4 Understanding the complex needs of patients—especially those with primary MF and the cytopenic phenotype—may require looking beyond the JAK-STAT pathway.4

JAK=janus kinase; STAT=signal transducer and activator of transcription.

More than one mechanism may promote MF.1,2

Considering the influence of driver mutations and other high-risk mutations, there is a need to continue developing a better understanding of additional cellular pathways and the distinct factors involved in primary MF.5,6 By doing so, researchers are focusing more on what may drive disease progression in each individual patient.1,2

Focusing exclusively on the JAK-STAT pathway may not adequately address the inflammatory aspects of the disease, such as NFκB activation and alternative pathways for STAT phosphorylation.1,7 However, some specific targets that are distinct from the JAK-STAT pathway—such as TLR/IL1R, ROCK, and FLT3—may require a closer look at the role they play in the inflammatory cascade of MF.1,2,8-10

FLT3=FMS-like tyrosine kinase 3; IL1R=interleukin-1 receptor; NFκB=nuclear factor kappa-light-chain-enhancer of activated B cells; ROCK=rho-associated coiled-coil kinase; TLR=toll-like receptor.
 
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How do you know when JAK inhibition may not be enough for your patients?4

By understanding each patient's type of myelofibrosis (primary or secondary), clinical phenotype (noncytopenic or cytopenic), and the genetic mutations/pathways involved, physicians can create a more appropriate management plan designed around each patient's needs.11,12

Research has shown that multiple pathways may be involved in MF.

JAK-STATPATHWAYTLR/IL1R-IRAK1PATHWAYRhoA-ROCK PATHWAYFLT3-STATPATHWAYIncrease in proinflammatory cytokines7,13Involved inmegakaryocyteand plateletformation8Activates genesimportant in cellsurvival10
TLR/IL1R-IRAK1PATHWAYJAK-STATPATHWAYRhoA-ROCKPATHWAYFLT3-STATPATHWAYIncrease in proinflammatorycytokines7,13Involved inmegakaryocyte and platelet formation8Activates genesimportant in cellsurvival10
IRAK1=interleukin-1 receptor-associated kinase 1; RhoA=Ras homolog family member A.

Consider the pathways to NFκB activation—and increased cytokine expression.

In patients with primary MF, JAK2V617F may be just one of many driver mutations to consider.12 JAK inhibition is focused on decreasing the signals of JAK2V617F and the resulting excess production of inflammatory cytokines.3 However, there may be other pathways that are causing STAT3 phosphorylation and NFκB transcription to continue, resulting in the overproduction of inflammatory cytokines and the subsequent constitutive activation of JAK1.1,13,14

JAK-STATPATHWAYTLR/IL1R-IRAK1PATHWAYJAK2STAT3STAT3PhosphorylationPhosphorylationJAKInhibitionIRAK1NFκBTranscriptionIncreased Cytokine ExpressionInhibition of any one pathway may not extinguish theproinflammatory microenvironment for patients with primary MF
JAK-STATPATHWAYTLR/IL1R-IRAK1PATHWAYSTAT3STAT3PhosphorylationPhosphorylationJAKInhibitionIRAK1NFκBTranscriptionIncreased Cytokine ExpressionInhibition of any one pathwaymay not extinguish theproinflammatorymicroenvironment for patientswith primary MFJAK2

Finding new perspective starts by
discovering other pathways.

Watch John Mascarenhas, MD, discuss how discovering complementary JAK-independent pathways has shaped his view of MF prognosis and progression.

Beyond-JAK-STAT video
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Exploring new pathways further develops insights around managing MF.1,2,8-10

As researchers continue to explore the complexity and evolving biology of MF, they discover different targets for future management of this disease. Research has brought to light potential complementary JAK‑independent pathways and somatic mutations, which may warrant further investigation.

Ongoing research is changing the future of MF.

Get in-depth, personal perspective from John Mascarenhas, MD and one of his patients as they share what ongoing research into MF means to them today and in the future.

Explore his story at InsideMF.com

References:
  1. 1. Singer JW, et al. Oncotarget. 2018;9(70):33416-33439.
  2. 2. Naymagon L and Mascarenhas J. HemaSphere. 2017;1(1):e1.
  3. 3. Mascarenhas J and Hoffman R. Clin Cancer Res. 2012;18(11):3008-3014.
  4. 4. Marcellino BK, et al. Clin Lymphoma Myeloma Leuk. 2020;20(7):415-421.
  5. 5. Masselli E, et al. Cells. 2020;9(9):2136.
  6. 6. Bose P and Verstovsek S. Int J Hematol. 2020;111(2):192-199.
  7. 7. Fisher DAC, et al. Leukemia. 2019;33(8):1978-1995.
  8. 8. Yang Q, et al. Exp Hematol. 2017;48:32-38.
  9. 9. Rocca S, et al. Mol Cancer. 2018;17(1):40.
  10. 10. Desterke C, et al. Cancer Res. 2011;71(8):2901-2915.
  11. 11. Pettit K and Odenike O. Curr Hematol Malig Rep. 2017;12(6):611-624.
  12. 12. Vainchenker W and Kralovics R. Blood. 2017;129(6):667-679.
  13. 13. Rhyasen GW and Starczynowski DT. Br J Cancer. 2015;112(2):232-237.
  14. 14. Lai HY, et al. Blood Adv. 2019;3(2):122-131.
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