Malignant hematopoietic cell lines: in vitro models for the study of MLL gene alterations

Human tumor cell lines are powerful tools for investigating basic and applied aspects of cell biology. Leukemia–lymphoma cell lines have been instrumental in the cytogenetic and molecular analysis of recurring chromosome rearrangements, notably translocations and inversions, thus illuminating the pathogenesis of hematological malignancy. Chromosomal translocations targeting the MLL gene at 11q23 have come to represent a paradigm in acute leukemias. These translocations result in the in-frame joining of the MLL gene with a partner gene to generate unique fusion proteins of putatively novel function. More than 30 partner genes that participate with MLL in the more than 60 known 11q23 translocations have been reported. Cell lines provide territory to both explore the detailed structures of 11q23 translocations and investigate the leukemogenic activities of MLL fusion proteins. We review here the leukemia cell lines that have been described to carry 11q23 translocations and MLL fusion genes. Except for the t(10;11)(p12;q23), each of the following relatively frequent 11q23/ MLL translocations is represented by one or more cell lines: 16 cell lines with t(4;11)(q21;q23), two cell lines with t(6;11)(q27;q23), seven cell lines with t(9;11)(p22;q23), and eight cell lines with t(11;19)(q23;p13). For each of three rare translocations, one cell line has been reported: t(5;11)(q15;q23), t(11;16)(q23;p13), and t(X;11)(q13;q23). Of these 36 cell lines with 11q23 translocations, 17 have been made available to us; we confirmed the occurrence of the alterations reported in these cell lines at the chromosomal and/or gene level. A second type of MLL gene alteration is the partial tandem duplication (PTD), which occurs in acute myeloid leukemia (AML). We found four AML cell lines with an MLL PTD; one acute lymphoblastic leukemia-derived cell line was reported to show a partial nontandem duplication. Finally, a third rearrangement involves intrachromosomal amplification of the unrearranged MLL gene leading to multiple copies of the gene and (presumably) increased expression. Three cell lines carrying such MLL amplifications have been described. The availability of these cell lines as model systems provides the opportunity to explore the altered expression or functions of MLL genes and their partners in oncogenesis.