Clinicopathological features and prognostic value of SOX11 in childhood acute lymphoblastic leukemia

Abstract

Acute lymphoblastic leukemia is marked by aberrant transcriptional features that alter cell differentiation, self-renewal, and proliferative features. We sought to identify the transcription factors exhibiting altered and subtype-specific expression patterns in BALL and report here that SOX11, a developmental and neuronal transcription factor, is aberrantly expressed in the ETV6-RUNX1 and TCF3-PBX1 subtypes of acute B-cell leukemias. We show that a high expression of SOX11 leads to alterations of gene expression that are typically associated with cell adhesion, migration, and differentiation. A high expression is associated with DNA hypomethylation at the SOX11 locus and a favorable outcome. The results indicate that SOX11 expression marks a group of patients with good outcomes and thereby prompts further study of its use as a biomarker. SOX11 is a transcription factor (TF) encoded by the SOX11 gene located in chromosome 2p25 1. It is a member of the SoxC (sex-determining region Y-related HMG box) group of genes and consists of two functional domains-the N-terminal DNA-binding and the C-terminal transactivation domains 2,3. Other SoxC family members include SOX4 and SOX12. Of these, SOX4 is a crucial TF in B lymphopoiesis and is expressed in the Band T-cell lineages 2,4,5. SOX11 is normally expressed in the developing central nervous system of the embryo, in keratinocytes, and in some other epithelial tissues 1,6-8. It is also expressed in ovarian and breast cancer, in which both tumor suppressor and oncogenic functions have been suggested 9,10. A knockout mouse model revealed the vital role of SOX11 during embryonic development, as SOX11-deficient mice died after birth likely from multiple heart defects, asplenia, and organ hypoplasia in the lungs, stomach, and pancreas 11. SOX11 deletions and mutations are associated with neurodevelopmental disorders 12. Previous studies have shown that SOX11 mRNA and nuclear protein expression is a specific marker for conventional but not indolent mantle cell lymphoma (MCL) 8,13-15. In MCL, SOX11 has been associated with either increased or reduced cell proliferation 16-23 and either good or bad prognosis 24-27. In a cohort of 50 adult acute myeloid leukemia (AML) patients, a high SOX11 expression was associated with FLT/ITD and NPM1 mutations and a shortened disease-free survival 28. There is other evidence linking SOX11 with B-lineage malignancies. Dictor et al. (2009) reported that the nuclear expression of SOX11 was found in eight cases of B-lymphoblastic neoplasias 29. Another study reported the strong nuclear expression of SOX11 in a single B-cell and five T-cell lymphoblastic lymphoma/leukemias 13. Vegliante et al. (2011) demonstrated the increased expression of SOX11 mRNA in ETV6-RUNX1 (E/R) and

Differential mRNA and long noncoding RNA expression profiles in pediatric B-cell acute lymphoblastic leukemia patients

“…It has been reported that the high expression of SOX11 leads to alterations of gene expression that are typically associated with cell adhesion, migration, and differentiation. Furthermore, its expression marks a group of patients with good outcomes [ 40 ]. Furthermore, Huang et al demonstrated that AML1-ETO-fused protein triggers the epigenetic silencing of the EYA4 gene, contributing to leukemogenesis in t (8;21) AML.…”

IGF2BP3 Associates with Proliferative Phenotype and Prognostic Features in B-Cell Acute Lymphoblastic Leukemia

“…The formalin-fixed and paraffin-embedded bone marrow trephine biopsy samples of the pediatric B-ALL patients were collected into a tissue microarray (TMA) with 1.5 mm punches (see also [ 21 ]), and 4-micrometer TMA sections were used for immunohistochemistry. An appendix was used as a control material for the IGF2BP3 and CD19/Ki-67 immunostainings.…”

“…The expression of BCL6 and pSTAT5 was semiquantitatively graded as negative when antigen was expressed in under 20% of leukemic blasts, and positive when expressed in over 20%. Clinical data and the flow cytometry data (e.g., CD34 expression) were retrieved from patient hospital records gathered as described previously [ 21 ]. The flow cytometry results were graded as either negative or positive.…”

Expression of BCL6 in paediatric B-cell acute lymphoblastic leukaemia and association with prognosis

“…17 For cases lacking the genetic subtype information, fluorescence in situ hybridisation analysis was performed on either BM aspiration samples or formalin fixed and paraffin embedded (FFPE) samples. 18…”

“…Three independent RNA expression datasets were used to analyse BCL6 gene expression as previously described: 18 (1) the Hemap dataset, which is a microarray dataset of 36 haematological malignancies that includes 6832 samples, including 662 paediatric and 642 adult B-ALL cases collected from different original studies that represent both high risk cohorts and those that include also common good prognosis subtypes; 19,20 (2) the PanALL study dataset, an RNA-sequencing dataset (n=1988), which includes 1234 paediatric and 754 adult B-ALL cases from different patient cohorts and therapy risk groups; 21 (3) a Nordic dataset, which consists of RNA-sequencing data from 115 paediatric B-ALL cases that represent cases diagnosed between the years 1996 and 2010 from different therapy risk groups. 22 The pre-BCR 'metagene' signature was studied in the Hemap and PanALL datasets, and included IGLL1, IGLL3, VPREB1, VPREB3, IGHM, SYK and ZAP70 genes, as described by Geng et al 9 Normalisation of the mRNA expression values has been described previously for the Hemap dataset 19,20 and the PanALL dataset.…”