Erythroid/megakaryocytic differentiation confers BCL-XL dependency and venetoclax resistance in acute myeloid leukemia

作者：Heikki A Kuusanmäki, Olli M. J. Dufva, Markus J. V. Vähä-Koskela, Aino‐Maija Leppä, Jani Huuhtanen, Ida Vänttinen, Petra Johanna Nygren, Jay Klievink, Jonas Bouhlal, Petri Pölönen, Qi Zhang, Shady Adnan Awad, Cristina Mancebo-Pérez, Joseph J Saad, Juho Jalmari Miettinen, Komal Kumar Javarappa, Sofia Aakko, Tanja M. Ruokoranta, Samuli Eldfors, Merja Heinäniemi, Kim Theilgaard‐Mönch, Ulla Wartiovaara‐Kautto, Mikko A. I. Keränen, Kimmo Porkka, Marina Konopleva, Krister Wennerberg, Mika Kontro, Caroline Akemi Heckman, Satu M. Mustjoki · 发表于：Blood · 年份：2022 · DOI：10.1182/blood.2021011094 · 被引用次数：132 · 研究领域：Acute Myeloid Leukemia Research、Chronic Lymphocytic Leukemia Research、Immune Cell Function and Interaction

Myeloid neoplasms with erythroid or megakaryocytic differentiation include pure erythroid leukemia, myelodysplastic syndrome with erythroid features, and acute megakaryoblastic leukemia (FAB M7) and are characterized by poor prognosis and limited treatment options. Here, we investigate the drug sensitivity landscape of these rare malignancies. We show that acute myeloid leukemia (AML) cells with erythroid or megakaryocytic differentiation depend on the antiapoptotic protein B-cell lymphoma (BCL)-XL, rather than BCL-2, using combined ex vivo drug sensitivity testing, genetic perturbation, and transcriptomic profiling. High-throughput screening of >500 compounds identified the BCL-XL-selective inhibitor A-1331852 and navitoclax as highly effective against erythroid/megakaryoblastic leukemia cell lines. In contrast, these AML subtypes were resistant to the BCL-2 inhibitor venetoclax, which is used clinically in the treatment of AML. Consistently, genome-scale CRISPR-Cas9 and RNAi screening data demonstrated the striking essentiality of BCL-XL-encoding BCL2L1 but not BCL2 or MCL1, for the survival of erythroid/megakaryoblastic leukemia cell lines. Single-cell and bulk transcriptomics of patient samples with erythroid and megakaryoblastic leukemias identified high BCL2L1 expression compared with other subtypes of AML and other hematological malignancies, where BCL2 and MCL1 were more prominent. BCL-XL inhibition effectively killed blasts in samples from patients with AML with eryt...