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Editorials
megakaryopoiesis and its overexpression engenders myelofibrosis in mouse models.13 Using a Thpo overexpres- sion model, Decker et al.14 showed that stromal deletion of PDGFRa or treatment with imatinib suppressed stromal cell expansion and ameliorated myelofibrosis. In addition to imatinib, other methods of targeting the PDGF pathway are currently under investigation in different fibrosis models, such as PDGF/PDGFR-blocking antibodies and aptamers.15
Dual targeting of JAK and JAK/platelet-derived growth factor downstream pathways
Primary myelofibrosis is caused by MPN phenotypic driver mutations (i.e. in JAK2, CALR or MPL) that result in constitutive activation of JAK-STAT signaling.16 Although JAK2 inhibitors such as ruxolitinib reduce constitutional symptoms and splenomegaly, and may stabilize myelofi- brosis, they do not have substantial disease-modifying activity in MPN. Inhibiting other tyrosine kinases including PDGF receptors is not sufficient either, since imatinib treat- ment in PMF was disappointing.17 A combinatorial approach involving JAK2 and PDGF inhibition in MPN could be considered, although hematologic toxicity is a real concern.18
An alternative treatment strategy involves simultaneous- ly inhibiting JAK-STAT and MEK-ERK signaling. A recent MPN preclinical study showed that JAK2 inhibitors induce a strong reduction in STAT signaling but only marginally reduce MEK/ERK signaling.19 Multiplexed analyses of 34 secreted factors in Jak2 V617F-mutant mice showed that transcript levels of the receptor Pdgfra, as well as the ligands Pdgfa and Pdgfb, were maintained in BM and spleen during ruxolitinib treatment.19 Additional experiments showed that PDGF signaling through MEK/ERK was not reduced upon ruxolitinib treatment. Combined treatment with JAK2 and MEK inhibitors was superior over inhibition with either compound alone in mouse models of Jak2 V617F and MPLW515-induced myelofibrosis, and reduced Pdgfra, Pdgfa, and Pdgfb transcript expression. These data suggest that combined MEK/JAK2 inhibition may be efficacious in treating MPN.
Conclusions and future directions
In conclusion, Kramer et al. have methodically and ele- gantly analyzed the sequential changes that occur in the BM during the initiation and progression of myelofibrosis in Gata1low mice and identified upregulation of the PDGF pathway as a hallmark of myelofibrosis. Their work sug- gests that increased PDGFR expression could be used as an early biomarker for myelofibrosis development. Given the paucity of reliable myelofibrosis biomarkers, this finding warrants further study in MPN patients. Additionally, now that next generation sequencing platforms are increasingly used to identify genetic predictors of progression to myelofibrosis in MPN, it would be interesting to study whether increased PDGF expression correlates with certain genetic subsets of MPN. Finally, given recent advancements enabling combined single-cell mutational and transcriptom- ic analyses,20 it will be possible to determine precisely which cellular sub-populations in the BM (both hematopoi- etic and stromal) are involved in PDGF signaling early in the course of myelofibrosis. Since a multitude of profibrotic factors are up-regulated in myelofibrosis, the therapeutic
efficacy of inhibiting a single pathway, especially in advanced disease, may be limited. However, the identifica- tion and early targeting of pathways that are activated dur- ing the initial stages of myelofibrosis may prove more fruit- ful.
Acknowledgments
AM acknowledges support from the NIH (R01HL131835), the MPN Research Foundation and the Gabrielle’s Angel Foundation for Cancer Research. Dr. Mullally is a Scholar of The Leukemia & Lymphoma Society.
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