KLF4: A new player in plasma cell development

KEYWORDS:

• antibody
• KLF4
• master regulators
• multiple myeloma
• plasma cells

This article refers to:

Forced KLF4 expression increases the generation of mature plasma cells and uncovers a network linked with plasma cell stage

Plasma cells are critical effectors of the adaptive immune system and are tasked with producing massive amounts of antibodies. Long-lived and quiescent plasma cells develop from B cell precursors in a process that also generates intermediate stage, cycling, and antibody-producing cells called plasmablasts.¹

Several transcription factors are thought to control plasmablast and plasma cell development. Such master regulators of plasma cells include XBP1, IRF4 and perhaps most importantly BLIMP1, a transcriptional repressor.1 All 3 factors are and specifically highly expressed in plasma cells and expressed at variable levels in plasmablasts.

In this volume of Cell Cycle, Schoenhals et al suggest the existence of a new master regulator of plasma cell development.² Using analysis of expression profiles, they found that the transcription factor KLF4 is expressed in human healthy bone marrow plasma cells. To study the role of KLF4 in plasma cell development, they leveraged an in vitro plasma cell differentiation model previously developed by the same group.³ This in vitro model faithfully recapitulates the cascade of events that occur in plasma cell differentiation, and most importantly provides an opportunity to perturb specific mechanisms, assess phenotypic consequences and conduct molecular analyses.

To investigate the role of KLF4 in the process of plasma cell differentiation, the authors transduced plasmablasts with a KLF4-expressing lentivirus. They then induced the plasmablasts to differentiate into plasma cells (PCs) using treatment with IL-6, IL-15 and IFNα as previously reported.3 Surprinsingly, enforcing KLF4 expression significantly increased production of both early PC and Long Lived Plasma Cells (LLPCs). The authors went on to show that KLF4 increases early PC and LLPC generation by reducing cell death (plasmablasts are typically short lived). This was accompanied by a reduction of effector caspase activity. The authors then used global transcriptomic analysis to identify candidate KLF4 target genes. While they only detected a handful of genes mobilized in KLF4 overexpressing early plasma cells versus KLF4 negative control cells, such genes formed a functionally coherent network enriched in genes with roles in cell cycle, cell morphology, cell function and maintenance and putatively driven by NUPR1, a factor that may control expression XBP1, one of the plasma cell master regulators.

Altogether the discovery of a new potential master regulator of plasma cell development has significant implications in our understanding of plasma cell development and diseases derived from plasma cells. However further investigations are needed to shed light on a number of areas. First and foremost, the role of KLF4 needs to be investigated in vivo in a model that capture the complex microenvironments and variety of exogenous signals that plasmablasts and plasma cells are exposed to. Second, the mechanisms by which KLF4 decreases cell death remain unclear. One possibility previously described is that KLF4 might be able to partially suppress p53 activity and thus reduce p53-mediated apoptosis⁴ A broader investigation of KLF4 target genes perhaps by combining Chromatin ImmunoPrecipitation followed by sequencing (ChIPseq) and transcriptome sequencing (RNAseq) may help identify additional direct and indirect KLF4 targets in plasma cells. Such analyses may help unravel connections with well-characterized master regulators of plasma cell development and identity such as BLIMP1. One hypothesis is that KLF4 cooperates with BLIMP1 and other plasma cell master regulators to enforce a more robust plasma cell expression program. Alternatively, the previously described non-transcriptional role of KLF4 in maintaining a higher-order chromatin structure⁵ may also be relevant to plasma cell development.

It is the hope that the results described in Schoenhals may eventually help shed some light on the role of KLF4 in plasma cell malignancies. The current data suggest a complex role. Consistent with its role in pre-B cells where KLF4 likely acts as a tumor suppressor by upregulating p21^CIP and down-regulating c-Myc and cyclin D2,⁶ KLF4 blocks proliferation when over-expressed in multiple myeloma cells.⁷ On the other hand certain multiple myeloma subtypes defined by gene expression profiles express high levels of KLF4. KLF4 expression status in myeloma cells may have clinical value since it is associated with melphalan and carfilzomib drug resistance in myeloma cells.⁷ KLF4s opposing protumorigenic or antitumor functions may thus be tightly controlled by condition-specific co-factors or signaling pathways whose identity remains to be uncovered.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.