Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia

Abstract

SummaryProgression to aggressive secondary acute myeloid leukaemia (sAML) poses a significant challenge in the management of myeloproliferative neoplasms (MPNs). Since the physiopathology of MPN is closely linked to the activation of interferon (IFN) signalling and that AML initiation and aggressiveness is driven by leukaemia stem cells (LSCs), we investigated these pathways in MPN to sAML progression. We found that high IFN signalling correlated with low LSC signalling in MPN and AML samples, while MPN progression and AML transformation were characterized by decreased IFN signalling and increased LSC signature. A high LSC to IFN expression ratio in MPN patients was associated with adverse clinical prognosis and higher colony forming potential. Moreover, treatment with hypomethylating agents (HMAs) activates the IFN signalling pathway in MPN cells by inducing a viral mimicry response. This response is characterized by double‐stranded RNA (dsRNA) formation and MDA5/RIG‐I activation. The HMA‐induced IFN response leads to a reduction in LSC signature, resulting in decreased stemness. These findings reveal the frequent evasion of viral mimicry during MPN‐to‐sAML progression, establish the LSC‐to‐IFN expression ratio as a progression biomarker, and suggests that HMAs treatment can lead to haematological response in murine models by re‐activating dsRNA‐associated IFN signalling.

Proof of concept of triple COMBI therapy to prohibit MPN progression to AML

“…By enhancing immune cell function, IFN in combination with Aza may further accelerate MPN cell killing. 8 Taken together, the study by de Castro et al 1 strengthens the concept of combination therapies in MPN and opens a new horizon for combination therapy by adding support to the concept that 'triple treatment' (IFN + Aza + ruxolitinib) might be a future treatment modality to be pursued in future well-designed clinical studies of patients in the accelerated/…”

“…These issues were studied using publicly available datasets. 1 Highly interesting, the authors find that high IFN signalling correlated with low LSC signalling in both MPN and AML samples, whereas MPN progression and AML transformation were featured by decreased IFN signalling and increased LSC signature. Treatment with a DNA hypomethylating agent (HMA) activated IFN signalling and reduced LSC signature in MPN cells with ensuing decreased colony-forming potential (Figure 1).…”

“…11 The present work by de Castro et al elegantly provides a mechanism for such synergy between IFN and Aza by increasing the IFN-alpha signalling. 1 The future treatment of MPN with the goal of inducing MRD 2,8 and hopefully cure in a subset of MPN patients are likely combination therapies concurrently targeting the malignant clone and reducing the inflammatory state, which is driving clonal expansion and disease progression. 2,3 Patients in the accelerated phase towards leukaemic transformation and patients having transformed to AML have a poor prognosis, although even in these stages, IFN monotherapy may be an option with the potential of reverting imminent or leukaemic transformation.…”

Recent Advances towards the Understanding of Secondary Acute Myeloid Leukemia Progression

“…Clonogenicity was significantly higher in this cohort compared with the rest of the study population, and the result was the same when comparing before and after transformation. The low IFN activity in these transforming cells also results in a more chaotic microenvironment where endothelial cells are dysregulated, and leukocytes are behaving abnormally while under increased oxidative stress [ 80 ].…”

“…Decitabine has also been used for treating MDS patients that have crossed the 20% blast threshold and progressed towards sAML as an alternative to chemotherapy. HMAs have also been shown to significantly decrease the progression from MPNs to sAML by inducing a viral mimicry response to upregulate IFN activity and reduce LSC levels [80,[133][134][135].…”