The Expression Pattern of the Pre-B Cell Receptor Components Correlates with Cellular Stage and Clinical Outcome in Acute Lymphoblastic Leukemia

PLoS One. 2016 Sep 9;11(9):e0162638. doi: 10.1371/journal.pone.0162638. eCollection 2016.

Abstract

Precursor-B cell receptor (pre-BCR) signaling represents a crucial checkpoint at the pre-B cell stage. Aberrant pre-BCR signaling is considered as a key factor for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) development. BCP-ALL are believed to be arrested at the pre-BCR checkpoint independent of pre-BCR expression. However, the cellular stage at which BCP-ALL are arrested and whether this relates to expression of the pre-BCR components (IGHM, IGLL1 and VPREB1) is still unclear. Here, we show differential protein expression and copy number variation (CNV) patterns of the pre-BCR components in pediatric BCP-ALL. Moreover, analyzing six BCP-ALL data sets (n = 733), we demonstrate that TCF3-PBX1 ALL express high levels of IGHM, IGLL1 and VPREB1, and are arrested at the pre-B stage. By contrast, ETV6-RUNX1 ALL express low levels of IGHM or VPREB1, and are arrested at the pro-B stage. Irrespective of subtype, ALL with high levels of IGHM, IGLL1 and VPREB1 are arrested at the pre-B stage and correlate with good prognosis in high-risk pediatric BCP-ALL (n = 207). Our findings suggest that BCP-ALL are arrested at different cellular stages, which relates to the expression pattern of the pre-BCR components that could serve as prognostic markers for high-risk pediatric BCP-ALL patients.

MeSH terms

  • Child
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • DNA Copy Number Variations / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic*
  • Heavy Chain Disease / genetics*
  • Heavy Chain Disease / metabolism
  • Humans
  • Immunoglobulin Light Chains, Surrogate / genetics*
  • Immunoglobulin Light Chains, Surrogate / metabolism
  • Immunoglobulin mu-Chains / genetics*
  • Immunoglobulin mu-Chains / metabolism
  • Neoplasm Staging
  • Oncogene Proteins, Fusion / metabolism
  • Pre-B Cell Receptors / genetics*
  • Pre-B Cell Receptors / metabolism
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Treatment Outcome

Substances

  • Core Binding Factor Alpha 2 Subunit
  • IGHM protein, human
  • IGLL1 protein, human
  • Immunoglobulin Light Chains, Surrogate
  • Immunoglobulin mu-Chains
  • Oncogene Proteins, Fusion
  • Pre-B Cell Receptors
  • RNA, Messenger
  • TCF3-PBX1 fusion protein, human
  • TEL-AML1 fusion protein
  • VPREB1 protein, human

Grants and funding

This work has been supported by grants from: Barncancerfonden (TJ2014-0083, DC, http://www.barncancerfonden.se), Cancerfonden (CAN2014/886, ILM, https://www.cancerfonden.se/), Assar Gabrielsson Fond (FB 15-57, DC, http://www.agfond.se/), Lions Cancerfond (2012:20, DC, http://www.lionscancerfond.se/), ALF (GBG, ILM, http://www.fou.nu/is/alfgbg), IngaBritt och Arne Lundbergs Forskning Stiftelse (ILM, http://www.lundbergsstiftelsen.se/en/home/), Stiftelsen Wilhelm och Martina Lundgrens Vetenskap (DC, http://www.wmlundgren.se/), Adlerbertska forskningsstiftelsen (DC, http://www.gu.se/forskning/stipendier/gustipendier/adlerbertska_forskningsstiftelsen). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.