The Calcitriol/Vitamin D Receptor System Regulates Key Immune Signaling Pathways in Chronic Lymphocytic Leukemia

Abstract

It has been proposed that vitamin D may play a role in prevention and treatment of cancer while epidemiological studies have linked vitamin D insufficiency to adverse disease outcomes in various B cell malignancies, including chronic lymphocytic leukemia (CLL). In this study, we sought to obtain deeper biological insight into the role of vitamin D and its receptor (VDR) in the pathophysiology of CLL. To this end, we performed expression analysis of the vitamin D pathway molecules; complemented by RNA-Sequencing analysis in primary CLL cells that were treated in vitro with calcitriol, the biologically active form of vitamin D. In addition, we examined calcitriol effects ex vivo in CLL cells cultured in the presence of microenvironmental signals, namely anti-IgM/CD40L, or co-cultured with the supportive HS-5 cells; and, CLL cells from patients under ibrutinib treatment. Our study reports that the calcitriol/VDR system is functional in CLL regulating signaling pathways critical for cell survival and proliferation, including the TLR and PI3K/AKT pathways. Moreover, calcitriol action is likely independent of the microenvironmental signals in CLL, since it was not significantly affected when combined with anti-IgM/CD40L or in the context of the co-culture system. This finding was also supported by our finding of preserved calcitriol signaling capacity in CLL patients under ibrutinib treatment. Overall, our results indicate a relevant biological role for vitamin D in CLL pathophysiology and allude to the potential clinical utility of vitamin D supplementation in patients with CLL.

Vitamin D and Cancer: An Historical Overview of the Epidemiology and Mechanisms

“…Concordantly with the association between low vitamin D status and poorer overall survival and progression-free survival in myeloid and lymphoid malignancies [ 161 ], in several types of leukemic cells, 1,25-(OH) 2 D 3 regulates essential pathways for survival and proliferation such as TLR, STAT1/3 or PI3K/AKT that are induced by immune cell–cell or cytokine activation [ 162 , 163 ].…”

The Absence of Retroelement Activity Is Characteristic for Childhood Acute Leukemias and Adult Acute Lymphoblastic Leukemia

“…In 3 out of 9 colorectal cancer samples, we previously identified tumor-specific L1 insertions using our method [24]. Additionally, we downloaded 7 normal bone marrow [28] and 6 chronic lymphocytic leukemia [29] whole-transcriptome data that were generated using the same approach (i.e., RNA-Seq of polyA fraction; the accession numbers GSE162427 and E-MTAB-1733, respectively). We down-sampled all the datasets to 4.5 million reads (smallest sample) and mapped the reads to the reference database L1base that includes transpositionallycompetent L1HS and L1PA2 [4].…”

“…The libraries were sequenced on Illumina NextSeq 550 (paired-end 75 + 75) generating from 17,805,150 to 18,351,291 sequencing reads per sample. In addition to three samples that were tested for new RE insertions in the present study, we used datasets that were obtained in other studies including 7 normal bone marrow [28] and 6 chronic lymphocytic leukemia [29] (accession number GSE162427 and E-MTAB-1733, respectively). Raw sequencing reads were processed with Cutadapt (https://doi.org/10.14806/ej.17.1 .200, accessed on 10 January 2022) to remove adapters and shorten reads to 75 + 75 nt to match the read length of our libraries.…”