B-cell development in the presence of the MLL/AF4 oncoprotein proceeds in the absence of HOX A7 and HOX A9 expression.
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.
Bertrand
F E
FE
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA.
Spengeman
J D
JD
Shah
N
N
LeBien
T W
TW
D001402:B-Lymphocytes / Q000473:pathology / Q000502:physiology*; D045744:Cell Line, Tumor; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D051788:Myeloid-Lymphoid Leukemia Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D011401:Promoter Regions, Genetic; D011519:Proto-Oncogenes; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors
C489900:Aff1 protein, mouse; D004268:DNA-Binding Proteins; C489213:HOXA5 protein, human; C115962:HOXA7 protein, human; C489815:HOXC8 protein, human; D018398:Homeodomain Proteins; C492047:Hoxa7 protein, mouse; C080041:Hoxc6 protein, mouse; C484113:Hoxd3 protein, mouse; C497422:KMT2A protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; C097899:homeobox protein HOXA9; C073547:HOXA4 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D011495:Histone-Lysine N-Methyltransferase