Chronic myeloproliferative neoplasms (MPNs) demonstrate a tendency for transformation to secondary acute myeloid leukemia (sAML). Little is known about the underlying mechanism for this transformation, resulting in few effective treatment options and a dismal prognosis with a median survival of <6 months. Consequently, there remains a critical need to define the mechanism responsible for the transition from chronic to aggressive disease.
Now a study from the Washington University School of Medicine in St. Louis has identified a molecule that may be the key to a strategy for preventing the chronic, slow-growing type of blood cancer from progressing to an aggressive form of leukemia (Nat Cancer 2023; https://doi.org/10.1038/s43018-022-00486-8).
In the study, researchers conducted a deep dive into the genetics of MPN and sAML patient stem and progenitor cells, both during the slow chronic phase and after the disease had transformed into the aggressive form while patients were taking JAK2 inhibitors. Through bulk and single-cell RNA sequencing analysis of serial MPN and sAML patient samples, the investigators discovered that the dual specificity phosphatase 6 (DUSP6) gene was highly expressed.
A variety of techniques, including cell culture, gene editing, and animal models were utilized to investigate the role of DUSP6 in leukemic progression and find new therapeutic targets for the treatment of leukemia. Pharmacologic DUSP6 targeting conferred an inhibition of S6 and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling and reduction of inflammatory cytokine production.
Researchers utilized this dependency pharmacologically via DUSP6 targeting across syngeneic and xenograft MPN and sAML models. These in vivo studies revealed that mice engrafted with CD34+ cells ectopically expressing DUSP6 propagate MPN disease severity and early lethality in patient-derived xenograft (PDX) models. In contrast, inhibition of DUSP6 effectively suppressed disease development across Jak2V617F and MPLW515L MPN mouse models and sAML PDXs without causing toxicity in healthy controls.
As the drug that inhibits DUSP6 is unavailable for human clinical trials, the team explored downstream molecules of DUSP6 as therapeutic targets that are required to perpetuate the negative effects of DUSP6. Ribosomal S6 kinase (RSK)1 was identified as a key downstream target of DUSP6 and a clinically important marker in AML prognosis. They demonstrated that inhibition of RSKI suppresses DUSP6 signaling in vitro and ex vivo. Together, this research emphasizes DUSP6 in directing disease transformation and highlights a therapeutic strategy of DUSP6-RSK1 axis targeting in MPNs and AML.
To gain additional insights into the study, Oncology Times reached out to senior author Stephen T. Oh, MD, PhD, Associate Professor of Medicine and Co-Chief of the Division of Hematology at the Washington University School of Medicine in St. Louis.
Oncology Times: MPNs exhibit a propensity for transformation to secondary AML. What are some of the factors that have made it challenging to understand how this transformation takes place?
Oh: "The acquisition of secondary mutations is clearly associated with disease transformation, but the manner in which particular mutation combinations may drive leukemic progression remains incompletely understood. Additional factors beyond specific mutations, such as aberrantly increased expression of DUSP6 as identified in our study, may play important roles in disease transformation. One challenge with understanding these factors is that most in vitro and in vivo models imperfectly recapitulate the human disease, in particular leukemic transformation."
Oncology Times: How do the findings of this study advance our knowledge of disease transformation?
Oh: "Our study uncovers a novel mediator of MPN disease transformation, DUSP6, which was aberrantly expressed in stem/progenitor cells from patients who transformed to secondary AML. We found that increased DUSP6 expression promoted advanced MPN disease features, while genetic and pharmacologic DUSP6 targeting suppressed MPN disease development. DUSP6 targeting additionally inhibited RSK1, which we found to be an essential driver of both MPNs and AML. This is particularly notable as a small molecule inhibitor of RSK kinases is currently in clinical trials."
Oncology Times: Why is the drug that directly inhibits DUSP6 not available for human clinical trials? What is an alternative therapeutic approach to inhibit the effects of DUSP6?
Oh: "The DUSP6 inhibitor we utilized in our studies, BCI, is thought to not be suitable for human studies, and I am not aware of any available alternative selective DUSP6 inhibitors. A more feasible strategy may be to target RSK1, and a small molecule RSK inhibitor (PMD-026) is currently in clinical trials for breast cancer."
Oncology Times: What are some limitations of the current study that you would like to address in future research?
Oh: "The current study establishes an important role for the DUSP6-RSK1 signaling axis in MPN disease pathogenesis. However, at this point, we don't fully understand the mechanisms by which these pathways promote aggressive disease development. We are currently conducting experiments seeking to determine whether aberrant signaling mediated by DUSP6-RSK1 is particularly relevant specifically within the stem/progenitor cell compartment and/or whether inflammatory cytokine production from mature myeloid cells may be a critical component. This has potential relevance for future therapeutic approaches targeting these pathways."
Dibash Kumar Das is a contributing writer.