Aberrant Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is implicated in the pathogenesis of acute myeloid leukemia (AML), a highly heterogeneous hematopoietic malignancy. The management of AML is complex and despite impressive efforts into better understanding its underlying molecular mechanisms, survival rates in the elderly have not shown a substantial improvement over the past decades. This is particularly due to the heterogeneity of AML and the need for personalized approaches. Due to the crucial role of the deregulated JAK-STAT signaling in AML, selective targeting of the JAK-STAT pathway, particularly constitutively activated STAT3 and STAT5 and their associated upstream JAKs, is of great interest. This strategy has shown promising results in vitro and in vivo with several compounds having reached clinical trials. Here, we summarize recent FDA approvals and current potential clinically relevant inhibitors for AML patients targeting JAK and STAT proteins. This review underlines the need for detailed cytogenetic analysis and additional assessment of JAK-STAT pathway activation. It highlights the ongoing development of new JAK-STAT inhibitors with better disease specificity, which opens up new avenues for improved disease management.

Signal transducer and activator of transcription 3 (STAT3) is frequently overexpressed in patients with acute myeloid leukemia (AML). STAT3 exists in two distinct alternatively spliced isoforms, the full-length isoform STAT3α and the C-terminally truncated isoform STAT3β. While STAT3α is predominantly described as an oncogenic driver, STAT3β has been suggested to act as a tumor suppressor. To elucidate the role of STAT3β in AML, we established a mouse model of STAT3β-deficient, MLL-AF9-driven AML. STAT3β deficiency significantly shortened survival of leukemic mice confirming its role as a tumor suppressor. Furthermore, RNA sequencing revealed enhanced STAT1 expression and interferon (IFN) signaling upon loss of STAT3β. Accordingly, STAT3β-deficient leukemia cells displayed enhanced sensitivity to blockade of IFN signaling through both an IFNAR1 blocking antibody and the JAK1/2 inhibitor Ruxolitinib. Analysis of human AML patient samples confirmed that elevated expression of IFN-inducible genes correlated with poor overall survival and low STAT3β expression. Together, our data corroborate the tumor suppressive role of STAT3β in a mouse model in vivo. Moreover, they provide evidence that its tumor suppressive function is linked to repression of the STAT1-mediated IFN response. These findings suggest that the STAT3β/α mRNA ratio is a significant prognostic marker in AML and holds crucial information for targeted treatment approaches. Patients displaying a low STAT3β/α mRNA ratio and unfavorable prognosis could benefit from therapeutic interventions directed at STAT1/IFN signaling.

Acute myeloid leukemia (AML) is the most common acute leukemia and is predominantly affecting the elderly. It is a heterogenous disease, showing a broad spectrum of genomic alterations and mutations that influence the clinical outcome and treatment options. The expression of the signal transducer and activator of transcription 3 (STAT3) is often dysregulated in AML and its constitutive activation is associated with poor outcome. Thus, STAT3 became an attractive therapeutic target but until now drugs targeting STAT3 only had moderate efficacy. This phenomenon might be related to the expression ratio of the two alternatively spliced isoforms: the full-length isoform STAT3α and the truncated version STAT3β, which play opposite roles in AML. In this study, we investigated the potential of selected, well-established drugs to impact the STAT3β/α ratio, as a higher STAT3β/α ratio is associated with better disease outcome. Atovaquone and selinexor independently elevated the STAT3β/α ratio and led to an upregulation of the STAT3β target gene SELL (CD62L). The combined treatment with atovaquone and selinexor entailed synergistic killing of AML cells in vitro and impaired the leukemic cell infiltration in vivo. Moreover, CD62L overexpression in a human AML cell line resulted in significantly prolonged survival in a xenograft mouse model. We propose that targeting the STAT3β/α ratio could be a promising new strategy for treating patients with AML and that the combination of selinexor and atovaquone could offer enhanced treatment outcomes.

Myeloproliferative neoplasms (MPNs) are chronic diseases characterized by an excessive production of myeloid blood cells. Janus kinase ( JAK2 ) ^V617F is the most common mutation in MPNs but a substantial proportion of patients harbour calreticulin ( CALR ) mutations—an attractive target for emerging immunotherapies. Natural killer (NK) cells have a central role in the elimination of malignant cells, but NK cells of MPN patients have reduced activity. Thus, reactivating their function might improve the disease outcome. Here, we demonstrate that NK cells from a CALR -mutant mouse model exhibit normal maturation but enhanced degranulation. Consistently, NK cells from CALR -mutant patients exhibit preserved degranulation ability, exceeding that observed in JAK2 -mutant patients. Notably, NK cells from CALR -, but not JAK2 -mutant patients express high levels of the immune checkpoint TIGIT possibly due to increased abundance of immunomodulatory proteins in the plasma. Moreover, CD34⁺ cells from MPN patients express elevated levels of the TIGIT ligand CD112. TIGIT blockade results in reduced platelet numbers in a transplant mouse model. These findings suggest that NK cells in CALR -mutant MPNs are activated but functionally constrained when encountering TIGIT ligand–expressing target cells, providing a strong rationale for exploring TIGIT blockade to restore NK-cell immunity in this disease subset.