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

被引:47
|
作者
Kuusanmaki, Heikki [1 ,2 ,3 ,4 ]
Dufva, Olli [2 ,3 ,5 ,8 ]
Vaha-Koskela, Markus [1 ]
Leppae, Aino-Maija [1 ,9 ,10 ]
Huuhtanen, Jani [5 ,6 ,7 ,11 ]
Vanttinen, Ida [1 ]
Nygren, Petra [5 ,6 ,7 ,12 ]
Klievink, Jay [5 ,6 ,7 ]
Bouhlal, Jonas [5 ,6 ,7 ]
Polonen, Petri
Zhang, Qi
Adnan-Awad, Shady [4 ,6 ,7 ,8 ]
Mancebo-Perez, Cristina [1 ]
Saad, Joseph [1 ]
Miettinen, Juho [1 ]
Javarappa, Komal K. [1 ]
Aakko, Sofia [1 ]
Ruokoranta, Tanja [1 ]
Eldfors, Samuli [16 ]
Heinaniemi, Merja [12 ]
Theilgaard-Monch, Kim [2 ,3 ,8 ,13 ,14 ]
Wartiovaara-Kautto, Ulla [17 ]
Keranen, Mikko [5 ,6 ,7 ,17 ]
Porkka, Kimmo [5 ,6 ,7 ,17 ]
Konopleva, Marina [15 ]
Wennerberg, Krister
Kontro, Mika
Heckman, Caroline A.
Mustjoki, Satu [5 ,6 ,7 ,8 ]
机构
[1] Univ Helsinki, Inst Mol Med Finland, Helsinki Inst Life Sci, Helsinki, Finland
[2] Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark
[3] Univ Copenhagen, Novo Nord Fdn Ctr Stem Cell Biol DanStem, Copenhagen, Denmark
[4] Fdn Finnish Canc Inst, Helsinki, Finland
[5] Helsinki Univ Hosp, Hematol Res Unit Helsinki, Comprehens Canc Ctr, Helsinki, Finland
[6] Univ Helsinki, Translat Immunol Res Program, Helsinki, Finland
[7] Univ Helsinki, Dept Clin Chem & Hematol, Helsinki, Finland
[8] iCAN Digital Precis Canc Med Flagship, Helsinki, Finland
[9] German Canc Res Ctr, Div Stem Cells & Canc, Heidelberg, Germany
[10] DKFZ ZMBH Alliance, Heidelberg, Germany
[11] Aalto Univ, Dept Comp Sci, Espoo, Finland
[12] Univ Eastern Finland, Inst Biomed, Sch Med, Kuopio, Finland
[13] Univ Copenhagen, Dept Hematol, Copenhagen, Denmark
[14] Univ Copenhagen, Finsen Lab, Rigshosp, Copenhagen, Denmark
[15] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX USA
[16] Harvard Med Sch, Massachusetts Gen Hosp, Canc Ctr, Charlestown, MA USA
[17] Helsinki Univ Hosp, Dept Hematol, Comprehens Canc Ctr, Helsinki, Finland
基金
芬兰科学院;
关键词
ACUTE MEGAKARYOCYTIC LEUKEMIA; ACUTE MEGAKARYOBLASTIC LEUKEMIA; WORLD-HEALTH-ORGANIZATION; TRANSCRIPTION FACTOR; CELL-DEATH; CANCER; EXPRESSION; GENE; ERYTHROPOIETIN; INHIBITOR;
D O I
10.1182/blood.2021011094
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 com-pounds 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 iden-tified 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 erythroid or megakaryocytic differentiation ex vivo and reduced tumor burden in a mouse erythroleukemia xenograft model. Combining the BCL-XL inhibitor with the JAK inhibitor ruxolitinib showed synergistic and durable responses in cell lines. Our results suggest targeting BCL-XL as a potential therapy option in erythroid/mega-karyoblastic leukemias and highlight an AML subgroup with potentially reduced sensitivity to venetoclax-based treatments.
引用
收藏
页码:1610 / 1625
页数:16
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