Human erythroleukemia genetics and transcriptomes identify master transcription factors as functional disease drivers

Abstract

Acute erythroleukemia (AML-M6 or AEL) is a rare but aggressive hematologic malignancy. Previous studies showed that AEL leukemic cells often carry complex karyotypes and mutations in known AML-associated oncogenes. To better define the underlying molecular mechanisms driving the erythroid phenotype, we studied a series of 33 AEL samples representing three genetic AEL subgroups including TP53-mutated, epigenetic regulator-mutated (e.g. DNMT3A, TET2 or IDH2), and undefined cases with low mutational burden. We established an erythroid vs. myeloid transcriptomics-based space in which, independently of the molecular subgroup, the majority of the AEL samples exhibited a unique mapping different from both non-M6 AML and myelodysplastic syndrome samples. Notably, more than 25% of AEL patients, including in the genetically-undefined subgroup, showed aberrant expression of key transcriptional regulators, including SKI, ERG, and ETO2. Ectopic expression of these factors in murine erythroid progenitors blocked in vitro erythroid differentiation and led to immortalization associated with decreased chromatin accessibility at GATA1 binding sites and functional interference with GATA1 activity. In vivo models showed development of lethal erythroid, mixed erythroid/myeloid or other malignancies depending on the cell population in which AEL-associated alterations were expressed. Collectively, our data indicates that AEL is a molecularly heterogeneous disease with an erythroid identity that results in part from the aberrant activity of key erythroid transcription factors in hematopoietic stem or progenitor cells.

Bcor deficiency perturbs erythro-megakaryopoiesis and cooperates with Dnmt3a loss in acute erythroid leukemia onset in mice

“…In contrast, the start of Gata1 expression coincides with the erythroid commitment and increases along with the erythroid differentiation. Collectively, these data provide evidence for an imbalance towards an erythroid phenotype starting from the LSK stage and point to Gata factors deregulation as an early event altering the HSC fate and sensitizing cells to further malignant transformation in the context of concurrent Bcor and Dnmt3a deficiency, as it has been also very recently demonstrated in both human and mouse AEL samples [45].…”

Nuclear interacting SET domain protein 1 inactivation impairs GATA1-regulated erythroid differentiation and causes erythroleukemia

“…Based on our findings one can speculate that in such cases the fusion may either act in a dominant-negative manner to NSD1 expressed from the non-arranged allele, or the presence of LOH is reducing NSD1 activity as recently reported for a significant number of solid cancers 21 . Interestingly, we also found aberrantly high SKI expression levels in tumor cells of some erythroleukemia patients, and that in vivo overexpression of a SKI ORF in BM-derived HSPC resulted in an erythroleukemia-like disease in mice, suggesting that SKI expression may not only be critical for impaired erythroid differentiation in Nsd1 −/− mice but also a driver of the human disease 62 . Collectively, our observations suggest that impaired NSD1 activity functionally interferes with lineage-associated transcriptional master regulators such as GATA1 resulting in impaired cellular differentiation as a first step to malignant transformation.…”

NSD1 in erythroid differentiation and leukemogenesis

“…Sequencing the epigenetic landscape of human erythroleukemia and functional in vitro and in vivo studies strongly proposes that different alterations ultimately converge to impaired GATA1 activity. 9 The NSD1 gene is located on the long arm of chromosome 5, a region that is the most frequent target of cytogenetic alteration in erythroleukemia cells. 10 It is, therefore, possible that reduced NSD1 activity (e.g.…”