Charles E. de Bock
The discovery that the gain of function JAK2 V617F mutation is present in myeloproliferative neoplasms (MPNs) has led to numerous clinical trials assessing the efficacy of JAK inhibitors. Most notably, ruxolitinib, a combined JAK1/2 selective inhibitor, has gained approval in patients with myeolofibrosis (MF), and additional JAK2 inhibitors including fedratinib, pacritinib, and momelotinib also under evaluation for patients with MF. However, while these inhibitors demonstrate some clinical benefit, they do not adequately reduce the mutant clone fraction. 1 , 2 Consequently, a critical question for the field has been whether the lack of a durable response is attributed to either (i) the inability of current JAK inhibitors to completely block the pathway or (ii) the possibility that mutant clones are not entirely dependent on this activated pathway.
To address these two possibilities, a new study from the laboratory of Ross Levine, published in Cancer Discovery, 3 developed an innovative mouse model of Jak2 V617F alone or in combination with Tet2 loss. The novel aspect of this mouse model lies in the ability to control the expression and genetic deletion of Jak2 V617F allele from mutant clones upon development of MPN. To do so, it utilizes two orthogonal site‐specific recombinases which exert precise control over the temporal expression and deletion of the Jak2 V617F allele.
The mouse model uses the well‐established Cre recombinase that recognises short nucleotide target sequences called Lox sites, in conjunction with the relatively new Dre recombinase which recognizes short nucleotide sequences called Rox sites. Importantly, the strategic arrangement and orientation of these sequences can lead to either flipping or deletion of the intervening DNA sequence. In this context, Dre recombinase is employed to initiate the expression of the Jak2 V617F allele. Subsequently, a modified CreER recombinase, translocated to the nucleus upon tamoxifen treatment, can delete the Jak2 V617F allele (Figure 1A). This intricate mouse model provided a powerful tool for comparing the durability of response between JAK inhibitors and the genetic loss of Jak2 V617F in the context of MPNs.