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

Abstract

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.

The MLL recombinome of adult CD10-negative B-cell precursor acute lymphoblastic leukemia: results from the GMALL study group

“…MLL-PTD is a fairly common aberration in AML and detected in 5% to 8% of cases, 22 but rarely, if ever, found in ALL. 23 The distribution of MLL aberrations differs markedly from that recently reported in infant (age Ͻ 1 year) ALL, where MLL aberrations were detectable by split fluorescent in situ hybridization (FISH), RT-PCR, or analysis of the MLL breakpoint region in 79% of 124 cases. 11 Forty-one percent of these infants showed an MLL-AF4, 18% an MLL-ENL, and 11% an MLL-AF9 fusion.…”

Mechanisms of Pinometostat (EPZ-5676) Treatment–Emergent Resistance in MLL-Rearranged Leukemia

“…Similar to a mechanism found for FLT3 inhibitors, preclinical studies performed with inhibitors of the PMT Enhancer of zeste homolog 2 (EZH2) demonstrated that one mechanism of drug resistance in this enzyme class is through the acquisition of secondary point mutations; whether such EZH2 resistancecausing mutations are relevant to the clinical situation is not clear at present (35,36). Following up on this work, we set out to examine whether MLL-r cell line models could acquire pinometostat resistance through continuous treatment at concentrations above the predetermined 14-day proliferation assay IC 90 (37). Resistance to pinometostat in all five cell lines tested emerged following 3 weeks of continued treatment and was defined by increased growth rates in the presence of inhibitor.…”

FLJ10849, a septin family gene, fuses MLL in a novel leukemia cell line CNLBC1 derived from chronic neutrophilic leukemia in transformation with t(4;11)(q21;q23)

“…4,5 At present, there are more than 60 partner genes for MLL. 4 Although the functions of the fusion transcripts remain largely unknown, it is thought for several reasons that the partner gene is critical for leukemogenesis.…”