Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-α in a murine model of polycythemia vera

Abstract

Key Points• IFNa targets Jak2V617F MPN stem cells.Interferon-a (IFNa) is an effective treatment of patients with myeloproliferative neoplasms (MPNs). In addition to inducing hematological responses in most MPN patients, IFNa reduces the JAK2V617F allelic burden and can render the JAK2V617F mutant clone undetectable in some patients. The precise mechanism underlying these responses is incompletely understood and whether the molecular responses that are seen occur due to the effects of IFNa on JAK2V617F mutant stem cells is debated. Using a murine model of Jak2V617F MPN, we investigated the effects of IFNa on Jak2V617F MPN-propagating stem cells in vivo. We report that IFNa treatment induces hematological responses in the model and causes depletion of Jak2V617F MPN-propagating cells over time, impairing disease transplantation. We demonstrate that IFNa treatment induces cell cycle activation of Jak2V617F mutant long-term hematopoietic stem cells and promotes a predetermined erythroid-lineage differentiation program. These findings provide insights into the differential effects of IFNa on Jak2V617F mutant and normal hematopoiesis and suggest that IFNa achieves molecular remissions in MPN patients through its effects on MPN stem cells. Furthermore, these results support combinatorial therapeutic approaches in MPN by concurrently depleting dormant JAK2V617F MPNpropagating stem cells with IFNa and targeting the proliferating downstream progeny with JAK2 inhibitors or cytotoxic chemotherapy. (Blood. 2013;121(18):3692-3702)

Analysis of Jak2 signaling reveals resistance of mouse embryonic hematopoietic stem cells to myeloproliferative disease mutation

“…The Li 2010 model presented with fewer phenotypic HSCs that were compromised in their reconstitution ability and self-renewal and had accumulated DNA damage, 20,34 whereas the Mullaly 2010 model observed no impact on HSC competitiveness despite an altered cycling status. 36,37 In the Marty 2010 model, an increase in HSC competitiveness was reported, 33 whereas the Tiedt 2008 model showed a complex HSC phenotype with an increase of phenotypic long-term HSCs that were less competitive, expressed a short-term HSC gene signature, and presented with an increase in DNA damage. 35 Using the Li et al and Kent et al models, 20,21,34 in which a HSC defect had been observed, it was striking to see that nascent HSCs are completely unaffected by the JAK2V617F mutation, even when present in 2 copies.…”

“…The effect of the JAK2V617F mutation on HSCs has been studied 20,21,[33][34][35][36][37] and was shown to compromise HSC function in one model, 20,34 a defect that is even more severe when homozygous. 21 Using the model, in which JAK2V617F is expressed from the mouse endogenous Jak2 locus following recombination with Stella-Cre, 21 we set out to determine how constitutively active JAK2 would affect embryonic HSPCs.…”

Recombinant interferon-α in myelofibrosis reduces bone marrow fibrosis, improves its morphology and is associated with clinical response

“…29 Flow cytometry and gene expression data demonstrate that this effect is mediated by the forced differentiation of neoplastic stem cells. The consequent exhaustion of the stem cell pool leads to a decrease of extra-medullary hematopoiesis, with a significant improvement of spleen size.…”

“…Thus, in myeloproliferative neoplasms, the therapeutic activity of recombinant interferon-α seems to be mediated more by the direct suppressive effects on neoplastic stem cells than by anti-inflammatory and/or immunoregulatory mechanisms. [29][30][31] The latter may, however, contribute to the clinical and histological response to recombinant interferon-α therapy, considering that increased levels of pro-inflammatory cytokines have an important role in the pathobiology of myeloproliferative neoplasms. 32 The interferon-mediated decrease of serum cytokines may thus resemble the anti-inflammatory effects of ruxolitinib, which are thought to be responsible for the improvement of spleen size after ruxolitinib administration.…”

Long-acting interferon for myeloproliferative neoplasms - an update

“…Preclinical data in mice model support that IFN preferentially depletes Jak2V617F MPN-propagating stem cells by activating cell cycle and promoting a predetermined erythroid-lineage differentiation program [6]. This was later shown to occur in humans by Prchal [7].…”