Hijack the HiJAKer: rethinking therapy for JAK2-mutant MPN Free

In this issue of Blood, Bonal et al¹ report on a mouse model of JAK2V617F-mutant myeloproliferative neoplasm (MPN) induced by low-level chimerism following bone marrow transplantation (BMT) of JAK2V617F cells into unconditioned homeostatic recipient mice. Using this approach that mimics somatically acquired clones in patients, the authors found that these JAK2V617F cells significantly affect both the recipient’s BM microenvironment and unmutated naïve hematopoiesis, thereby skewing the recipient’s nonmutant hematopoietic system toward an MPN-like phenotype. These findings will have major implications for MPN therapy.

Bcr-Abl1–negative MPNs include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF). JAK2V617F is the most prevalent driver mutation. The spectrum of JAK2V617F mutant disease ranges from the clonal hematopoiesis of indeterminate potential (CHIP) without signs of disease to early MPN (such as ET and PV) characterized by disease-related blood abnormalities and symptoms to progressive MPN with considerable splenomegaly and increasing BM MF culminating in blast phase MPN.² Multiple factors, including allelic burden, genetic predisposition, secondary mutation, and chronic inflammation, have been shown to contribute to MPN risk and development, making it challenging to study MPN disease initiation and progression.

JAK2V617F mouse models have significantly improved our understanding of MPN disease development and the involved cellular and molecular mechanisms.^3-6 However, there is a paucity of mouse models that recapitulate sustained low variant allele frequency (VAF) of early MPN development without disturbing the microenvironment induced by pretransplant irradiation. Bonal et al report such a model in which unfractionated BM-derived CD45.2 JAK2V617F cells were transplanted into unconditioned CD45.1 recipient mice. The recipient mice developed a low VAF-driven PV phenotype after a long latency at 28-32 weeks, thus more faithfully mimicking the development of MPN in patients than other mouse models employing BMT into irradiated mice.

Importantly, with low donor cell chimerism and the absence of recipient conditioning, JAK2V617F cells affected the recipient BM microenvironment and unmutated naïve hematopoiesis. The BMT of CD45.2 JAK2V617F cells caused the skewing of non-JAK2V617F CD45.1 recipient cells toward an MPN phenotype, as revealed by RNA sequencing (RNA-seq) analysis 28 to 32 weeks post-BMT. Non-JAK2V617F CD45.1 recipient–derived cells showed an upregulation of erythroid and myeloid genes, similar to that observed in CD45.2 JAK2V617F mutant donor–derived cells. RNA-seq analysis of the BM stroma of the recipient mice revealed a loss of osteo-mesenchymal transcripts, and microcomputed tomography imaging confirmed the loss of trabecular bone structure, suggesting an irreversible change in the BM microenvironment and bone structure.

These results align with a study by Kleppe et al⁷ using a JAK2V617F transplant mouse model with irradiated recipients, which demonstrated that aberrant cytokine production from both malignant JAK2V617F mutant and nonmutant hematopoietic cells contributed to the MPN phenotype. The inhibition of the JAK-STAT pathway with the JAK inhibitor ruxolitinib normalized cytokine production in both malignant JAK2V617F mutant and nonmutant cells, indicating that the inhibition of cytokine production in both cell types is required to achieve a therapeutic response.

The experimental design used by Bonal et al should result in innovative in-depth studies on mutant clone residence and expansion, CHIP, and MPN disease progression. Moreover, the observation that JAK2V617F mutant cells effectively affect hematopoiesis supporting the BM stroma and skew the non-JAK2V617F hematopoietic system toward an MPN-like phenotype is particularly relevant for pharmacological intervention. To date, drug development targets the disease-causing clone and aberrant JAK2-STAT signaling.⁸ The results reported by Bonal et al reinforce the assertion that drug development should target not only the mutated malignant clone but also the skewed “hijacked,” unmutated bystander cells.⁹ For example, targeting and eliminating the aberrant altered megakaryocytes, the major drivers of the MPN proinflammatory milieu and MF,^1,10 might be a step in this direction. Obviously, this requires new avenues and strategies of MPN treatment, particularly because the current clinical development is focused on more specific anti-MPN therapies, such as those selectively targeting the CALR- and JAK2V617F mutant clones.

Conflict-of-interest disclosure: S.K. reports receiving research grant funding from Novartis; consulting fees from Pfizer, Incyte, Novartis, CTI BioPharma, and GlaxoSmithKline (GSK); payments or honoraria from Novartis, Pfizer, Incyte, and GSK; travel or accommodation support from Novartis, Incyte, AOP Pharma, CTI BioPharma, Pfizer, GSK, and Sierra Oncology; and participating in advisory boards for Pfizer, Incyte, Novartis, CTI BioPharma, Bayer, GSK, and Sierra Oncology. M.Z. declares no competing financial interests.