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Abstract The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens selective and pan-histone deacetylase inhibitors (HDACis) emerge as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, here we dissect the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstitute the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 (PA2G4) protein. PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogates EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACis-based combination therapies in patients with 3q26 AML.

IntroductionPolycythemia vera (PV) is a JAK2-mutated myeloproliferative neoplasm (MPN) characterized by clonal erythrocytosis and an intrinsic risk of transformation into acute myeloid leukemia (AML), known as blast-phase (BP) disease, a condition typified by dismal prognosis. In PV, the evolution to BP generally occurs through an overt fibrotic progression, represented by the post-PV myelofibrotic (MF) stage. However, direct leukemic transformation from PV may also occur in up to ~50% of patients. In this study, we sought to shed light on the morphological, clinical, and molecular features that may differentiate BP arising from a direct transition from the PV stage (post-PV-BP) from those evolving through a diagnosis of post-PV myelofibrosis (post-PV-MF-BP). Methods and resultsWe retrospectively analyzed a cohort of post-PV-BP (n=5) and post-PV-MF-BP (n=5). We found that BP arising from PV directly displayed significantly lower leukocyte count (median 2.93 × 109/L, range: 2.30–39.40 vs. median 41.05 × 109/L, range: 5.46–58.01; P=0.03), and spleen diameter (14.0 cm, range: 11.5–20.0 vs. 25.5 cm, range: 18–26; P=0.03) as compared to those experiencing an overt fibrotic stage. The most striking differences emerged from bone marrow (BM) morphological analysis: all post-PV-BP were characterized by significantly higher cellularity (median 70%, range: 60%–98% vs. 28%, range: 2%–41%, P=0.0245), lower degree of fibrosis (fibrosis grade 1 vs. fibrosis grade 3 in all cases, P=0.008) and dysplastic features involving all three lineages, most prominently the erythroid and megakaryocytic compartment. Next-generation sequencing (NGS) analysis revealed that post-PV-BP cases were enriched in mutations located in genes involved in DNA methylation such as DNMT3A, IDH1/2, and TET2 (45% vs. 15%, P=0.038). DiscussionWith all the limits of the small number of patients for each cohort, our data suggest that BPs that arise directly from PV present a peculiar phenotype, consistent with the molecular signature of the disease, typified by mutations of genes occurring with a high frequency in Myelodysplastic Syndromes (MDS) and MDS/MPN. Further studies in larger cohorts are warranted to translate these observations into robust evidence that may advise therapeutic choices.