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