We have recently shown that the amounts of most gene products are precisely regulated during the development of hematopoietic cells in the bone marrow [1, 2]. Comparing the intensities of antigens (gene products) on cells of the same maturational stages, the variability within an individual exceeds that of the variability of the means between individuals. These data show that not only is the timing of appearance of gene product expression during hematopoiesis precise, but the absolute amounts of expression of most gene products are invariant from individual to individual, independent of age and marrow stress. The single antigen studied that differed from all others was CD33, which demonstrated a broad variability in quantitative expression from individual to individual even though the within patient variability was low.

The intensity of CD33 expression has been identified to significantly affect the response of AML patients to treatment with Gemtuzumab ozogamicin (GO, Mylotarg)[3]. Pediatric patients with the lowest amounts of CD33 expression did not show a benefit when treated with this antibody-toxin conjugate. We have recently demonstrated that a pair of SNPs, in linkage disequilibrium (LD), is also related to the cell surface intensity expression of CD33 on the diagnostic leukemia cells as well as response to therapy [4]. The CD33 SNP rs12459419 (C< T) is present in exon 2 and results in an alanine to valine change at codon 14. This SNP is found within 4bp of the intron-1/exon-2 junction, and resides within exon splicing enhancer binding site for splicing factor-SRSF2. Presence of the variant T results in altered splicing resulting in skipping of exon2, and thus a shorter CD33-isoform (D2-CD33) that lacks the IgV-domain [5-7]. Interestingly, exon2-encoding IgV-domain contains the epitope for the p67. 6-CD33 antibody, which is used both for diagnostic immunophenotyping and also for the humanized