CDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia

• Published in: EMBO molecular medicine 2022-04, Vol.14 (4), p.e14990-n/a
• Main Authors: He, Lixiazi, Arnold, Christian, Thoma, Judith, Rohde, Christian, Kholmatov, Maksim, Garg, Swati, Hsiao, Cheng‐Chih, Viol, Linda, Zhang, Kaiqing, Sun, Rui, Schmidt, Christina, Janssen, Maike, MacRae, Tara, Huber, Karin, Thiede, Christian, Hébert, Josée, Sauvageau, Guy, Spratte, Julia, Fluhr, Herbert, Aust, Gabriela, Müller‐Tidow, Carsten, Niehrs, Christof, Pereira, Gislene, Hamann, Jörg, Tanaka, Motomu, Zaugg, Judith B, Pabst, Caroline
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; AML; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; CD34 antigen; CDC2 Protein Kinase - antagonists & inhibitors; CDK7 inhibition; Cell self-renewal; Cyclin-Dependent Kinases - antagonists & inhibitors; Drug Synergism; EMBO03; EMBO37; EMT gene; Epigenetics; Gene expression; Genomes; GPR56; Hedgehog protein; Hedgehog Proteins - metabolism; Hedgehog Proteins - therapeutic use; Humans; Leukemia; leukemia stem cell; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Medical prognosis; Mesenchyme; Mutation; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Protein expression; Protein Kinase Inhibitors - pharmacology; Proteins; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins c-bcl-2 - therapeutic use; self‐renewal; Stem cells; Sulfonamides - pharmacology; Surface markers; Synergism; Wnt protein
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.202114990

The heterogeneous response of acute myeloid leukemia (AML) to current anti‐leukemic therapies is only partially explained by mutational heterogeneity. We previously identified GPR56 as a surface marker associated with poor outcome across genetic groups, which characterizes two leukemia stem cell (LSC)‐enriched compartments with different self‐renewal capacities. How these compartments self‐renew remained unclear. Here, we show that GPR56 + LSC compartments are promoted in a complex network involving epithelial‐to‐mesenchymal transition (EMT) regulators besides Rho, Wnt, and Hedgehog (Hh) signaling. Unexpectedly, Wnt pathway inhibition increased the more immature, slowly cycling GPR56 + CD34 + fraction and Hh/EMT gene expression, while Wnt activation caused opposite effects. Our data suggest that the crucial role of GPR56 lies in its ability to co‐activate these opposing signals, thus ensuring the constant supply of both LSC subsets. We show that CDK7 inhibitors suppress both LSC‐enriched subsets in vivo and synergize with the Bcl‐2 inhibitor venetoclax. Our data establish reciprocal transition between LSC compartments as a novel concept underlying the poor outcome in GPR56 high AML and propose combined CDK7 and Bcl‐2 inhibition as LSC‐directed therapy in this disease. Synopsis RNA‐ and ATAC‐seq profiling combined with functional in vitro and in vivo studies unravel the multi‐faceted roles of GPR56, a surface marker associated with high leukemia stem cell (LSC) burden and poor prognosis in acute myeloid leukemia (AML). ATAC‐seq profiling of 35 primary AML specimens links high GPR56 expression to Wnt and Hh signaling. GPR56 is required for in vitro and in vivo expansion of primary human AML cells. GPR56 enhances besides RhoA also TGFB, Hedgehog, and Wnt pathway activities, which inhibit each other to coordinate reciprocal transition between the GPR56 + CD34 + and GPR56 + CD34 − compartments to sustain the LSC pool. CDK7 inhibitors synergize with the Bcl‐2 inhibitor venetoclax to suppress both GPR56 + LSC‐enriched compartments in vitro and in vivo . Graphical Abstract RNA‐ and ATAC‐seq profiling combined with functional in vitro and in vivo studies unravel the multi‐faceted roles of GPR56, a surface marker associated with high leukemia stem cell (LSC) burden and poor prognosis in acute myeloid leukemia (AML).