Abstract
The D-type cyclins (CCND1, CCND2, and CCND3) in association with CDK4/6 are known drivers of cell cycle progression. We reported previously that inactivation of FOXO1 confers growth arrest and apoptosis in B-ALL, partially mediated by subsequent depletion of CCND3. Given that previously the canonical MYC target CCND2 has been considered to play the major role in B-ALL proliferation, further investigation of the role of FOXO1 in CCND3 transcription and the role of CCND3 in B-ALL is warranted. In this study, we demonstrated that CCND3 is essential for the proliferation and survival of B-ALL, independent of the mutational background. Respectively, its expression at mRNA level exceeds that of CCND1 and CCND2. Furthermore, we identified FOXO1 as a CCND3-activating transcription factor in B-ALL. By comparing the effects of CCND3 depletion and CDK4/6 inhibition by palbociclib on B-ALL cells harboring different driver mutations, we found that the anti-apoptotic effect of CCND3 is independent of the kinase activity of the CCND3-CDK4/6 complex. Moreover, we found that CCND3 contributes to CDK8 transcription, which in part might explain the anti-apoptotic effect of CCND3. Finally, we found that increased CCND3 expression is associated with the development of resistance to palbociclib. We conclude that CCND3 plays an essential role in the maintenance of B-ALL, regardless of the underlying driver mutation. Moreover, downregulation of CCND3 expression might be superior to inhibition of CDK4/6 kinase activity in terms of B-ALL treatment.
Highlights
B-cell lymphoblastic leukemia (B-ALL) is the most common pediatric neoplasia [1]
Cyclin D3 (CCND3) is the highest expressed D-Cyclin in all subtypes of B-ALL To clarify the role of D-type cyclins in B-ALL, we compared their expression at mRNA level in the most common B-ALL subtypes (Fig. 1A)
CCND3 was expressed at much higher levels than CCND1 and CCND2 in all B-ALL subtypes
Summary
Pediatric B-ALL is associated with longterm survival of over 90%, whereas adult B-ALL shows dismal outcomes with cure rates below 40% [2]. Therapy in both children and adults typically consists of combinatory administration of cytostatic agents [3], which in many cases induce life treating toxicity and complications. We reported previously that the tightly regulated expression of the transcription factor forkhead box protein O1 (FOXO1) is essential for the maintenance of B-ALL [5]. Our data were later corroborated in a BCR-ABL1transformed B-ALL mouse model with inducible Foxo deletion [7]. We demonstrated that genetic and pharmacological inhibition of FOXO1 downregulates Cyclin D3 (CCND3) expression and the cytotoxic effects of FOXO1 depletion could be ameliorated by CCND3 overexpression [5]
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