Abstract
We reported previously that increased expression of aldehyde dehydrogenase 1 (ALDH1) in multiple myeloma (MM) is a marker of tumor-initiating cells (TICs) that is further associated with chromosomal instability (CIN). Here we demonstrate that member A1 of the ALDH1 family of proteins, ALDH1A1, is most abundantly expressed in myeloma. Enforced expression of ALDH1A1 in myeloma cells led to increased clonogenicity, tumor formation in mice, and resistance to myeloma drugs in vitro and in vivo. The mechanism underlying these phenotypes included the ALDH1A1-dependent activation of drug-efflux pump, ABCB1, and survival proteins, AKT and BCL2. Over expression of ALDH1A1 in myeloma cells led to increased mRNA and protein levels of NIMA-related kinase 2 (NEK2), whereas shRNA-mediated knock down of NEK2 decreased drug efflux pump activity and drug resistance. The activation of NEK2 in myeloma cells relied on the ALDH1A1-dependent generation of the retinoid X receptor α (RXRα) ligand, 9-cis retinoic acid (9CRA) - not the retinoic acid receptor α (RARα) ligand, all-trans retinoic acid (ATRA). These findings implicate the ALDH1A1-RXRα-NEK2 pathway in drug resistance and disease relapse in myeloma and suggest that specific inhibitors of ALDH1A1 are worthy of consideration for clinical development of new approaches to overcome drug resistance in myeloma.
Highlights
Multiple myeloma (MM), a difficult-to-treat and in most cases incurable neoplasm of the hematopoietic bone marrow, is characterized by clonal expansion of malignant, antibody-producing plasma cells
We sought to determine whether ALDH1A1 is the chief representative of the aldehyde dehydrogenase 1 (ALDH1) family in two human myeloma cell lines (HMCLs) that were selected for mechanistic studies on myeloma drug resistance: ARP1 and OPM1
We took advantage of the Aldefluor® assay, which relies on flow sorting to fractionate cells that exhibit ALDH1 activity from cells that do not (ALDH1-) [14], to separate ARP1 and OPM1 cells according to ALDH1 status and used Quantitative reverse-transcription PCR (qPCR) analysis to show that ALDH1A1 is more highly expressed in ALDH1+ than ALDH1- cells (Figure 1D)
Summary
Multiple myeloma (MM), a difficult-to-treat and in most cases incurable neoplasm of the hematopoietic bone marrow, is characterized by clonal expansion of malignant, antibody-producing plasma cells. Myeloma cells exhibit numerous gene expression changes and cytogenetic aberrations that frequently affect the immunoglobin heavy-chain locus on chromosome 14 as well as loci on chromosomes 1, 13 and 17 [2,3,4,5]. Additional drivers of drug resistance include aberrant expression of transcription factors, mutations in tumor suppressor genes and distorted cell cycle regulation [7]. Despite these advances, additional research is warranted to enhance our understanding of the genetic pathways of myeloma drug resistance
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