Infant acute lymphoblastic leukemia (ALL) is frequently characterized by the t(4;11)(q21;q23) cytogenetic abnormality encoding the MLL/AF4 oncogene, increased HOX gene expression and a pro-B/monocytoid phenotype. We have previously established a novel MLL/AF4-positive cell line, B-lineage 3 (BLIN-3), which retains several features of normal B-lineage development (functional Ig gene rearrangement and apoptotic sensitivity to stromal cell withdrawal) not generally observed in Infant ALL. We now use microarray analysis to identify patterns of gene expression in BLIN-3 that may modulate MLL/AF4 oncogenesis and contribute to the retention of normal B-lineage developmental characteristics. Comparison of 6815 expressed genes in BLIN-3 with published microarray data on leukemic blasts from t(4;11) patients indicated that BLIN-3 was unique in lacking the expression of certain HOX-A cluster genes. These results were validated by RT-PCR showing no expression of HOX A7 or HOX A9 in BLIN-3. A HOX C8 promoter reporter was active in BLIN-3, indicating that lack of HOX gene expression in BLIN-3 was not due to a nonfunctional MLL/AF4. Our results suggest that B-lineage development can proceed in t(4;11) leukemic blasts in the absence of HOX-A gene expression.
Bibliographical noteFunding Information:
We thank John Kersey, Paula Croonquist, Michael Linden, Brian Van Ness, Kevin Roberg-Perez (University of Minnesota Cancer Center) and Paul Doran (Affymetrix) for helpful discussions. We also thank Jay Hess (University of Pennsylvania) for kindly providing the Hox C8-Luc vector. This work was supported by National Institutes of Health Grant RO1 CA31685 (TWL) and the Leukemia Research Fund (TWL), University of Minnesota. FEB was supported by the Chris P Tkalcevic Foundation for Leukemia Research as a Special Fellow of the Leukemia and Lymphoma Society. TWL holds the Apogee Enterprises Chair in Cancer Research.
- B-cell development