Molecular Landscapes and Models of Acute Erythroleukemia

Abstract

Malignancies of the erythroid lineage are rare but aggressive diseases. Notably, the first insights into their biology emerged over half a century ago from avian and murine tumor viruses-induced erythroleukemia models providing the rationale for several transgenic mouse models that unraveled the transforming potential of signaling effectors and transcription factors in the erythroid lineage. More recently, genetic roadmaps have fueled efforts to establish models that are based on the epigenomic lesions observed in patients with erythroid malignancies. These models, together with often unexpected erythroid phenotypes in genetically modified mice, provided further insights into the molecular mechanisms of disease initiation and maintenance. Here, we review how the increasing knowledge of human erythroleukemia genetics combined with those from various mouse models indicate that the pathogenesis of the disease is based on the interplay between signaling mutations, impaired TP53 function, and altered chromatin organization. These alterations lead to aberrant activity of erythroid transcriptional master regulators like GATA1, indicating that erythroleukemia will most likely require combinatorial targeting for efficient therapeutic interventions.

Figure 1.

Genetic landscape of human AEL. Schematic representation of the most prevalent genetic lesions reported in human AEL patients.^,,,, Alterations of the TP53 tumor suppressor were found in ≥30% of AEL and in the majority PEL patients. Note: only the studies by Iacobucci et al and Montalban-Bravo et al included patients with leukemia diagnosed as PEL (according to the WHO 2016 classification). AEL = acute erythroleukemia; PEL = purely erythroid leukemia.

Figure 2.

Chronology of AEL mouse models. Schematic timeline of tumor virus-induced, unexpected, and rational erythroleukemia mouse models. r = viral overexpression; tg = transgenic; ge = genome editing; kd = knock-down; MuLV = murine leukemia virus; AEL = acute erythroleukemia.

Figure 3.

Targeted therapeutic strategies emerging from the epigenomic landscapes and AEL disease models. Schematic representation of major players identified to date in human AEL and the potential strategies for targeted interference, including (1) blocking aberrant activation of the JAK/STAT signaling axis (upper left); (2) restoration of the tumor suppressive TP53 activity (upper right); (3) inhibition of epigenetic regulators (lower left); and (4) reactivation of impaired activity of erythroid master transcription factors (like GATA1) to boost terminal differentiation of malignant erythroblasts (lower right). AEL = acute erythroleukemia.