Abstract

Simple SummaryNew therapies have greatly improved the progression-free and overall survival for patients with “standard risk” multiple myeloma (MM). However, patients with “high risk” MM, in particular patients whose MM cells harbor non-functional p53, have very short survival times because of the early relapse and rapid development of highly therapy-resistant MM. In this report, we identify a novel mechanism responsible for Growth Factor Independence-1 (GFI1) regulation of the growth and survival of MM cells through its modulation of sphingolipid metabolism, regardless of their p53 status. We identify the Sphingosine-1-Phosphate Phosphatase (SGPP1) gene as a novel direct target of GFI1 transcriptional repression in MM cells, thus increasing intracellular sphingosine-1-phosphate levels, which stabilizes c-Myc. Our results support GFI1 as an attractive therapeutic target for all types of MM, including the “high risk” patient population with non-functional p53, as well as a possible therapeutic approach for other types of cancers expressing high levels of c-Myc.Multiple myeloma (MM) remains incurable for most patients due to the emergence of drug resistant clones. Here we report a p53-independent mechanism responsible for Growth Factor Independence-1 (GFI1) support of MM cell survival by its modulation of sphingolipid metabolism to increase the sphingosine-1-phosphate (S1P) level regardless of the p53 status. We found that expression of enzymes that control S1P biosynthesis, SphK1, dephosphorylation, and SGPP1 were differentially correlated with GFI1 levels in MM cells. We detected GFI1 occupancy on the SGGP1 gene in MM cells in a predicted enhancer region at the 5’ end of intron 1, which correlated with decreased SGGP1 expression and increased S1P levels in GFI1 overexpressing cells, regardless of their p53 status. The high S1P:Ceramide intracellular ratio in MM cells protected c-Myc protein stability in a PP2A-dependent manner. The decreased MM viability by SphK1 inhibition was dependent on the induction of autophagy in both p53WT and p53mut MM. An autophagic blockade prevented GFI1 support for viability only in p53mut MM, demonstrating that GFI1 increases MM cell survival via both p53WT inhibition and upregulation of S1P independently. Therefore, GFI1 may be a key therapeutic target for all types of MM that may significantly benefit patients that are highly resistant to current therapies.

Highlights

  • Multiple myeloma (MM) is the second most common hematological malignancy [1]and the most frequent cancer involving bone

  • We found that Growth Factor Independence-1 (GFI1) acts as a direct repressor of SGPP1 gene transcription in MM cells, which increased the intracellular S1P levels regardless of the MM cell’s p53 status

  • To determine the potential of GFI1-dependent modulation of sphingolipid metabolism to promote survival of MM cells, we evaluated the transcriptional expression of genes coding for the main enzymes that control intracellular S1P levels, SphK1 and SGPP1, in MM cell lines with altered GFI1 expression

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Summary

Introduction

Multiple myeloma (MM) is the second most common hematological malignancy [1]and the most frequent cancer involving bone. Identifying new therapeutic targets in MM patients that can overcome drug resistance is critically needed. Growth Factor Independence 1 (GFI1) is a Zn-finger DNA binding protein with an. N-terminal SNAG domain that recruits repressive chromatin modifiers, such as lysine demethylase 1 (LSD1, KDM1A), to target genes to exert its role as a transcriptional repressor [6]. GFI1 is known for its critical roles in hematopoietic stem cells as well as in the development, specification, and function of multiple hematopoietic lineages by repressing key target genes [7,8]. High levels of GFI1 in T and B cells abolish G1 cell cycle arrest and apoptosis induced by growth factor withdrawal [7,9]. High levels of GFI1 have been associated with supporting the viability of both types of acute lymphoblastic leukemia (ALL) in the presence of initiating oncogenes

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