CDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia.
Lixiazi HeChristian ArnoldJudith ThomaChristian RohdeMaksim KholmatovSwati GargCheng-Chih HsiaoLinda ViolKaiqing ZhangRui SunChristina SchmidtMaike JanssenTara MacRaeKarin HuberChristian ThiedeJosée HébertGuy SauvageauJulia SpratteHerbert FluhrGabriela AustCarsten Müller-TidowChristof NiehrsGislene PereiraJörg HamannMotomu TanakaJudith Barbara ZauggCaroline PabstPublished in: EMBO molecular medicine (2022)
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.
Keyphrases
- acute myeloid leukemia
- stem cells
- fatty acid
- gene expression
- cell cycle
- allogeneic hematopoietic stem cell transplantation
- cell proliferation
- epithelial mesenchymal transition
- electronic health record
- big data
- cell therapy
- dna methylation
- bone marrow
- peripheral blood
- transcription factor
- single cell
- machine learning
- mesenchymal stem cells
- chronic lymphocytic leukemia
- signaling pathway
- high intensity
- acute lymphoblastic leukemia
- genome wide
- network analysis
- smooth muscle