Mechanisms of B-cell arrest in acute lymphoblastic leukaemia (ALL) of childhood - The interplay between the essential early B-cell factor EBF1 and the multifunctional zinc finger protein OAZ

Abstract

A specific form of childhood leukaemia is the precursor B-lineage acute lymphoblastic leukaemia (pre-B ALL), in which progenitors of the B-lymphocytes go awry. Previous transcriptome-wide analyses on ALL patient samples showed an aberrant activation of the BMP2-dependent pathway in the leukaemic cells. The goal of the present study was to assess the biological relevance of BMP2 signalling and its potential transcriptional targets in ALL of childhood. We hypothesised that an activated BMP2-pathway either reflects a state of differentiation of leukaemic cells or rather a specific aberration of ALL which drives and maintains the malignant phenotype. During this work it was discovered that BMP2 and its signalling target OAZ were highly expressed in TEL/AML1 rearranged ALL patient samples in comparison to normal haematopoietic stem cell and B-cell progenitor control samples. OAZ is normally not expressed in haematopoietic cells implying a potential role of OAZ in the pathogenesis of ALL. Aberrant activity of OAZ might block the EBF1-mediated transcriptional activation of target genes, which are essential for normal B-cell differentiation and development. The net effect could be a maturation arrest, one of the characteristic features of leukaemia. A first hit-event like the TEL/AML1 rearrangement in HSCs or B-cell progenitors, followed by an aberrant expression of OAZ through still undefined mechanisms, might be sufficient or at least contribute to the initiation or propagation of leukaemia. The first step in the functional analysis of OAZ expression recapitulated recent knowledge and showed the specific interaction of OAZ and EBF1 on the protein level, disrupting EBF1 function by sequestration. Further significant OAZ expression was detectable in engrafted ALL cells that were serially transplanted into NOD/scid mice. For the first time it was possible to show that OAZ expression in haematopoietic progenitors in an in-vitro culture based system was able to inhibit B-cell differentiation and to significantly downregulate the gene expression of the direct EBF1 target genes CD79a, CD79b, IGLL1 and VpreB necessary for proper B-cell development. Further in-vitro and in-vivo studies which allow for modulation of OAZ activity on the background of the TEL/AML1 rearrangement in haematopoietic cells might be able to define the role of OAZ as a bona fide target in leukaemia development and may lead to alternative, innovative treatment strategies directed towards its deleterious effects on B-cell differentiation.