ASH 2024 | Potential therapeutic targets to improve the prognosis of patients with acute erythroid leukemia

Acute erythroid leukemia is a high-risk of leukemia subtype characterized by predominant expansion of erythroblasts in the bone marrow. There are still many controversies in its diagnosis, with continuous changes in the classification criteria. This is a poor prognostic form of leukemia with a lack of well-known therapeutic targets and a lack of effective therapeutic options. A few years ago, we described a landscape of genetic alterations that characterize this subtype, with the main one being represented by TP53 mutations, which are biallelic in most cases, and they are often accompanied by complex karyotype, by mutations in many other genes, such as epigenetic regulators, transcription factors, signaling genes. So, TP53 mutations confer very poor outcome that make this subtype resistant to conventional chemotherapeutic approaches. By CRISPR dependency studies, it has been shown that this leukemia has a very high dependency on BCL2L1, which encodes for BCLXL and is an anti-apoptotic protein, which can be targeted by inhibitors of these pathways, such as inhibitors of BCLXL, dual BCL2 BCLXL inhibitors, providing a good promising option for these patients. We also established, since acute erythroid leukemia models are rare, by CRISPR-Cas9 of recurrently mutated genes, we used genome editing to recreate these mutations and faithfully recapitulate in preclinical models this very high-risk leukemia. And we use these models that are more faithful representation of the human leukemia to do and explore more the therapeutic intervention by high-throughput drug screening. But also, we perform CRISPR genome-wide screening to understand which targets they may be relevant to the disease. And interestingly, indeed, we found that the heme biosynthesis, which is important for production of heme within erythroid cells, was one of the top dependencies for survival in these cells. With the genes like UROD, there was upregulated by some functional characterization. We were able to show that inhibition of this pathway may trigger cells to that, providing a potential targetable protein that can be pursued for therapeutic intervention.

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