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Blood, 1 December 2001, Vol. 98, No. 12, pp. 3398-3405
NEOPLASIA
Pro-B-cell to pre-B-cell development in B-lineage acute
lymphoblastic leukemia expressing the MLL/AF4 fusion protein
Fred E. Bertrand,
Christine Vogtenhuber,
Nisha Shah, and
Tucker W. LeBien
From the University of Minnesota Cancer Center and the
Department of Laboratory Medicine and Pathology, University of
Minnesota, Minneapolis.
The most common chromosomal abnormality of infant acute
lymphoblastic leukemia (ALL) is the t(4;11)(q21;q23) that gives rise to
the MLL/AF4 fusion gene. Leukemic blasts expressing MLL/AF4 are arrested at an early progenitor stage with lymphoid or monocytoid characteristics. A novel B-lineage ALL cell line termed
B-lineage-3 (BLIN-3) requiring
human bone marrow (BM) stromal cell contact and interleukin-7 (IL-7)
for optimal proliferation has been established. BLIN-3 cells have a
CD19+/CD10 phenotype typical of infant ALL,
and they harbor the t(4;11)(q21;q23) chromosomal translocation. Reverse
transcription-polymerase chain reaction and Western blot analysis
confirmed the presence of the MLL/AF4 fusion mRNA and
protein in BLIN-3. Initial BLIN-3 cultures had a pro-B cell phenotype
and did not express cytoplasmic or surface µ heavy chain. After
approximately 5 months in culture on BM stromal cells plus IL-7, BLIN-3
sublines emerged expressing µ heavy chain and VpreB on the cell
surfaces (ie, pre-B-cell receptor [BCR]+). BLIN-3 cells
expressing pre-BCR had the t(4;11)(q21;q23) translocation and expressed
the MLL/AF4 fusion protein. Cross-linking the BLIN-3 pre-BCR led to
enhanced cell proliferation, demonstrating that BLIN-3 expressed a
functional pre-BCR. Increased acquisition of surface pre-BCR in BLIN-3
sublines was associated with loss of DJ rearrangements and the
appearance of VDJ rearrangements. These results indicate that
expression of the MLL/AF4 fusion protein is compatible with BM stromal
cell and cytokine dependency, functional immunoglobulin gene segment
rearrangement, and subsequent expression of a potentially diverse
antigen receptor repertoire. Thus, the expression of MLL/AF4 is
compatible with the normal developmental program of human B-lineage cells.
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