Anti-leukemic effect of CDK9 inhibition in T-cell prolymphocytic leukemia

Abstract

T-cell prolymphocytic leukemia (T-PLL) is an aggressive malignancy characterized by chemotherapy resistance and a median survival of less than 2 years. Here, we investigated the pharmacological effects of the novel highly specific cyclin-dependent kinase 9 (CDK9) inhibitor LDC526 and its clinically used derivate atuveciclib employing primary T-PLL cells in an ex vivo drug sensitivity testing platform. Importantly, all T-PLL samples were sensitive to CDK9 inhibition at submicromolar concentrations, while conventional cytotoxic drugs were found to be largely ineffective. At the cellular level LDC526 inhibited the phosphorylation at serine 2 of the RNA polymerase II C-terminal domain resulting in decreased de novo RNA transcription. LDC526 induced apoptotic leukemic cell death through down-regulating MYC and MCL1 both at the mRNA and protein level. Microarray-based transcriptomic profiling revealed that genes down-modulated in response to CDK9 inhibition were enriched for MYC and JAK-STAT targets. By contrast, CDK9 inhibition increased the expression of the tumor suppressor FBXW7, which may contribute to decreased MYC and MCL1 protein levels. Finally, the combination of atuvecliclib and the BCL2 inhibitor venetoclax exhibited synergistic anti-leukemic activity, providing the rationale for a novel targeted-agent-based treatment of T-PLL.

T‐cell prolymphocytic leukemia is associated with deregulation of oncogenic microRNAs on transcriptional and epigenetic level

“…The miRNAs identified herein are significantly enriched for miRNAs reported by RNA-seq (hypergeometric distribution, p ≤ 0.05). [16][17][18] Remarkably, we observed a better overlap of differentially expressed miRNAs with miRNA-sequencing studies than with the array-based studies (Fischer's exact test, p < 0.05). We found overlap and differences between the T-PLL samples and the T-cell leukemia cell lines, SUP-T11 and JURKAT.…”

“…16,17 Another recent array-based miRNA expression profiling study described 17 differentially expressed miRNAs in T-PLL compared to the healthy CD3+ T-cells. 18 Here, we employed an orthogonal technique, that is, ribonuclease protectionbased assay, to investigate the expression of 2083 miRNAs in T-PLL samples and normal T-cell populations. Moreover, to explore the reasons for miRNA deregulation in T-PLL; we integrated genomic data as well as epigenomic profiles of T-PLL.…”

“…Two recent studies using small RNA sequencing reported 34 and 35 miRNAs to be deregulated in T‐PLL as compared to normal CD3+ and effector CD4+ T‐cells, respectively 16,17 . Another recent array‐based miRNA expression profiling study described 17 differentially expressed miRNAs in T‐PLL compared to the healthy CD3+ T‐cells 18 . Here, we employed an orthogonal technique, that is, ribonuclease protection‐based assay, to investigate the expression of 2083 miRNAs in T‐PLL samples and normal T‐cell populations.…”

T-Cell Prolymphocytic Leukemia: An Overview of Current and Future Approaches

“…Targeted epigenetic therapies (such as EZH2 inhibitors), tumor suppressor (CHEK2, FBXW10, and SAMHD1) enhancers, P53 de-repressors, and many other rationale-based techniques are currently being studied with potential for future treatment in many hematologic malignancies including T-PLL [16,[33][34][35][36][37].…”

Hijacking the Pathway: Perspectives in the Treatment of Mature T-cell Leukemias

“… 8 , 29 In T-PLL, the high preclinical activity of SNS-032 (Sunesis Pharmaceuticals) (CDK2, CDK7, CDK9 inhibitor) and of LDC526 (Bayer AG) (CDK9 inhibitor) showed associations with myelocytomatosis viral oncogene homolog (MYC) expression levels and inhibited MYC downstream pathways. 8 , 30 CDK9 inhibition led to downregulation of the anti-apoptotic protein MCL1, implicating a combined use of CDK inhibitors with BH3 mimetics. To our knowledge, there is no published data on clinical activity of CDK inhibitors in T-PLL or T-LGL.…”