Dysregulated Class I histone deacetylases are indicators of poor prognosis in multiple myeloma

Abstract

Abbreviations:Histone deacetylases (HDAC) control gene expression through their ability to acetylate proteins, thereby influencing a diverse range of cellular functions. Class I HDAC (HDAC1-3 and 8) and HDAC6 are predominantly upregulated in malignancies and their altered expression in some cancers has a significant prognostic implication. The expression and prognostic consequence of dysregulated Class I HDAC and HDAC6, key players in multiple myeloma (MM), are unknown. This study hypothesized that HDAC are dysregulated in MM and patients with high expression have significantly poorer prognostic outcomes. Quantitative PCR for 11 HDAC (Class I, II, and IV) was performed in genetically heterogeneous human myeloma cell lines (HMCL) and primary MM and compared to normal plasma cells (PC). In HMCL, HDAC1-3 and 8 (Class I), and HDAC5 and HDAC10 (Class II) were significantly upregulated compared to normal PC. In primary MM, the median expression level of all of the HDAC, except HDAC1 and HDAC11, were elevated when compared to normal PC. Patients with higher levels of HDAC1-3, HDAC4, HDAC6, and HDAC11 transcripts demonstrated a significantly shorter progression-free survival (PFS). Immunohistochemical staining for HDAC1 and HDAC6 on bone marrow trephines from a uniformly treated cohort of transplant eligible MM patients revealed that HDAC1 protein was detectable in most patients and that higher levels of MM cell HDAC1 protein expression (90 % versus 20 % MM cell positivity) correlated with both shorter PFS (P D 0 .07) and shorter overall survival (P D 0 .003). Conversely, while the majority of patients expressed HDAC6, there was no correlation between HDAC6 levels and patient outcome. Together, these results indicate that overexpression of Class I HDAC, particularly HDAC1, is associated with poor prognosis in MM.

Mining the Plasma Cell Transcriptome for Novel Cell Surface Proteins

“…Isolation of bone marrow mononuclear cells (BMMNC), determination of MM cell proportion and isolation of CD138 + cells from MM cells and plasma cells from healthy donors was performed as previously described [47]. Briefly, Ficoll Plaque Plus (GE Healthcare, Chicago, IL, USA) was utilized to isolate BMMNC as per manufacturer’s guidelines.…”

Epigenetic regulatory mutations and epigenetic therapy for multiple myeloma

“…In general histone acetylation is associated with transcriptional activation, and recent investigations revealed that HDAC1, 2, 3 and 6 are highly expressed in MM contributing to the malignant phenotype (91). Conversely, mutations in the HAT CREBBP appear more common in relapsed MM and gene copy loss of CREBBP and EP300 is observed in 10% MM patients (Figure 1).…”

Panobinostat: First Global Approval

“…Higher levels of HDAC activity are associated with the silencing of differentiation and tumour suppressor genes, leading to oncogenesis [1]. Increased HDAC levels have been reported in several human tumours and cancer cell lines [2][3][4], including multiple myeloma [5]. Panobinostat (Farydak Ò ) is a nonselective HDAC inhibitor [6], a relatively new class of anticancer agents.…”