Targeting cistrome and dysregulated transcriptome of post-MPN sAML

Pathogenic mutations in JAK2, MPL or calreticulin associated with activated JAK/STAT3/5 signaling are a common feature in Myeloproliferative Neoplasms (MPNs) [1]. Pivotal clinical trials confirmed the activity, leading to FDA approval, of the type I JAK1/2 inhibitor ruxolitinib as therapy for advanced MPN-Myelofibrosis (MF) and Polycythemia Vera [1]. Ruxolitinib confers notable clinical benefit and may improve patient survival in MPN-MF. However, adverse side effects, persistence of JAK2/STAT3/5 signaling with reduced responsiveness, and progression to secondary (s) AML are associated with loss of clinical utility of ruxolitinib [1]. While lacking additional mutations in JAK2, JAKi-persister/resistant MPN-MF or sAML cells exhibit reactivation of JAK2STAT3/5 signaling due to trans-phosphorylation of JAK2 by JAK1 or TYK2 tyrosine kinases [2]. JAKi-persister/ resistant cells exhibit dependency on heat shock protein 90 (HSP90) chaperone complex and collateral sensitivity to HSP90 inhibitor [2]. Co-mutations in TP53, ASXL1, TET2, IDH2 and SRSF2 are associated with poorer outcome in ruxolitinib-treated MF-MPN and with higher risk of AML transformation (sAML), which develops in up to 20% of patients with MPN-MF [3]. Ruxolitinib or standard anthracycline/Ara-C-based chemotherapy is only modestly active and displays limited impact on clinical outcome in sAML, which has a median survival of less than 6 months [3]. Therefore, alternative and more effective treatments are needed for sAML. It should be noted that heightened JAK2/STAT3/5 signaling and cooccurrence of mutations in epigenetic modifiers, i.e., ‘epimutations’, could potentially create the dysregulated transcriptome responsible for the aggressive phenotype and treatment-refractoriness of sAML (Figure 1) [4]. What is the underlying molecular basis of the dysregulated transcriptome in post-MPN sAML, and how could this be therapeutically approached? Activation of multiple transcription factors (TFs), including lineage specific master regulators, MYC and signaling TFs such as STAT3/5 and RELA, and their collaborative binding to enhancers and promoters leads to recruitment of transcriptional cofactors including HATs (histone acetyltransferases) [4, 5] (Figure 1). HAT such as CBP/p300 induces acetylation of lysine residues on the histone H3 and H4 proteins and TFs [4, 5]. BRD4 and BRD2 are members of the bromodomain extraterminal (BET) family of reader proteins (BETP) that recognize and bind to acetylated lysines on histone proteins and TFs [5]. BETPs assemble transcriptional co-factors, including mediator protein and pTEFb (positive transcript elongation factor b), at super-enhancers/enhancers and promoters, thereby inducing RNA pol II (RNAP2)-mediated mRNA transcript elongation, especially of super-enhancerdriven oncogenes, including c-Myc, Cyclin D1, Bcl-xL, PIM1 and CDK4/6 that are important for cell growth and survival of AML cells, including post-MPN sAML cells (Figure 1) [4, 5]. BRD4 has also been shown to bind acetylated RELA and be essential for NFκB transcriptional activity, which is involved in the cytokine production and biology of post-MPN sAML cells [1, 5]. Several structure/ Editorial