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

Abstract

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.

GRaNIE and GRaNPA: Inference and evaluation of enhancer-mediated gene regulatory networks applied to study macrophages

“…We next assessed the cell-type specificity GRaNIE-inferred eGRNs. To this end, we obtained datasets in different cell types with matched RNA and chromatin accessibility data for primary human CD4+ T-cells (44) and from acute myeloid leukaemia (AML) (45) and (46). We ran GRaNIE using the same parameters as described above and obtained additional eGRNs for primary CD4+ T-cells (Table S5) and for AML (Table S6).…”

“…We obtained raw RNA-seq data for 23 AML patients from (90). Processed and quality-controlled ATAC-seq data and peaks for the same patients was obtained from (46).…”

“…Processed quantitative phosphoproteomics data from polarising THP1-derived macrophages was obtained from (46).…”

DNA Damage Response−Related Proteins Are Prognostic for Outcome in Both Adult and Pediatric Acute Myelogenous Leukemia Patients: Samples from Adults and from Children Enrolled in a Children’s Oncology Group Study

“…CDK1_2_3.pT14 upregulation in the poorest surviving CC patient clusters of the DDR-related protein networks ( Figure 5 A) may signal enhanced cell cycle regulation and increased opportunity to perform DDR, thus highlighting the relevance of CDK inhibition in AML. A study published in 2022 showed that CDK7 inhibitors suppressed both leukemia stem cell (LSC)-enriched subsets in vivo and synergized with the BCL-2 inhibitor venetoclax [ 42 ]. Further studies are needed to examine potential CDKi synergy with chemotherapeutic agents such as Cytarabine and Doxorubicin, which may help to improve therapy response among select CC patients.…”

“…Several protein inhibitors may be appropriate when considering therapy options for either CC or VH patients. For our CC patients, higher CDK1_2_3.pT14 levels associated with poorer OS and thus the efficacy of CDK inhibitors such as THZ531, THZ1, YKL-5-124, and LDC4297, may likely merit further investigation in the context of chemotherapy-treated AML patients [ 42 ]. In VH patients, low levels of CDKN1B and CDKN1B.pS10 differentiated two poor surviving clusters from a favorable cluster ( Figure 5 D,E).…”