Selective reduction of JAK2V617F-dependent cell growth by siRNA/shRNA and its reversal by cytokines

Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms

“…For instance, Jedidi et al have recently demonstrated that cytokines capable of signaling through JAK1 can convey resistance to JAK2-targeted therapies. 16 Moreover, analogous to certain examples of cytokine signaling, these 2 JAKs can interact and may activate one another. 14,15 Interestingly, here we show, for the first time, that JAK1 is hyperactivated in the peripheral blood of MF patients, although the mechanism is currently an area of ongoing investigation.…”

“…14,15 Interestingly, cytokines capable of signaling through JAK1/2 have recently been shown to convey resistance to inhibition of JAK2V617F with siRNA or TKIs, suggesting a cell autonomous benefit of JAK1/2 inhibition. 16 Moreover, it has been documented that patients with primary myelofibrosis (MF) have extremely high levels of circulating inflammatory cytokines, such as IL-6 and tumor necrosis factor-␣ (TNF-␣), [17][18][19][20] and these cytokines are probably responsible for the hypercatabolic state and constitutional symptoms, such as weight loss and fatigue, frequently seen in patients with MF. 21 Recognizing that many of these proinflammatory cytokines use JAK1, and to some extent also JAK2, we hypothesize that selective inhibition of both kinases may provide greater clinical benefit.…”

IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms

“…Although availability of secreted IL-33 in the niche has yet to be demonstrated, we clearly show that nuclear IL-33 is expressed to a greater extent in the BM of newly diagnosed BCR-ABL1-negative MPN patients compared with controls. Since MPN stem/progenitor cells display hypersensitivity to cytokines and growth factors, similarly to SHIP-deficient HSCs and myeloid progenitor cells (2,23), it is conceivable that even low amounts of secreted IL-33 within the niche may suffice to initiate ST2-dependent inflammation that supports MPNs.…”

“…In vitro, cells from MPN patients are characterized by an intrinsic independence and/or hypersensitivity to growth-factor stimulation and cytokine stimulation (2,3). In CML cells, the BCR-ABL1 protein stimulates constant autocrine production of IL-3, IL-6, G-CSF, and TNF (3)(4)(5).…”

Constitutive JunB expression, associated with the JAK2 V617F mutation, stimulates proliferation of the erythroid lineage

“…40 Erythroid precursor cells, cultured during 4 days as described above, were incubated with the viral supernatant for 24 h. On day 5, GFP þ /CD36 þ /Gpa À cells were sorted after immunostaining with specific antibodies (Immunotech, Marseille Luminy, France) with a cell sorter (FACSDiva, Becton Dickinson, Le Pont de Claix, France). Lentivirusmediated short hairpin RNAs were also used to down-modulate JUNB or JAK2 V617F (Jedidi et al, submitted) 41 expression in parental, JAK2 WT-or JAK2 V617F-expressing Ba/F3-EPOR cells.…”