Overexpression of dominant-negative Ikaros 6 protein is restricted to a subset of B common adult acute lymphoblastic leukemias that express high levels of the CD34 antigen.

Ikaros is a critical regulator of hematopoiesis. Its effects result in part from the balance between the isoforms that are produced by differential splicing of the pre-mRNA. Short isoforms that lack the DNA-binding domain act as dominant negatives by binding long isoforms through the C-terminal zinc-finger domain, which allows for the homo- or heterodimerization of the proteins. There are a number of evidences that different subsets of murine hematopoietic progenitors - as defined by phenotype - have different patterns of Ikaros expression. Forced expression of short isoforms (Ik5, Ik6 or Ik7) in murine or human hematopoietic progenitors alters the differentiation capacities of these cells. Human leukemias provide additional information: because of the blockade in differentiation, leukemias represent an equivalent of a particular stage of human hematopoietic hierarchy. We and others have shown that human acute leukemias are heterogeneous for the pattern of Ikaros isoform expression. The present study focused on adult de novo B ALLs and the Ikaros 6 isoform. ProB (BI, n=3), common B (BII, n=15) and preB (BIII, n=3) ALL were identified by their phenotype. RT-PCR and Western blot analyses of blast cell protein lysates suggest that approximately 50% of BII leukemias overexpress Ikaros 6 RNA and protein. Comparison of BII cells with high or normal levels of Ik6 shows a higher level of expression for the membrane stem cell antigen CD34 in the former, as detected with flow cytometry and confirmed with DNA arrays.