A 5-year-old girl was diagnosed with acute myeloid leukemia (AML) characterized by a variant t(8;21) translocation. The patient achieved remission, and is now, 4 years later, still in ongoing remission. However, a follow-up control of the bone marrow 15 months after diagnosis revealed a new clone characterized by the MLL rearrangement t(11;11)(q13;q23). To exclude the possibility of a secondary AML, numerous bone marrow control samples were subsequently investigated over a 30-month period. During this period, the amount of MLL rearranged cells was decreasing from 50% to 20% as determined by karyotype and fluorescence in situ hybridization (FISH) analysis. Morphology was unsuspicious without any sign for a secondary malignancy in all samples.
The breakpoint region of the MLL partner gene could be mapped to chromosome 11 at band q13 (Figure 1A). Using a newly developed restriction enzyme fragment length polymorphism–based cloning strategy, a new MLL partner gene was identified as ARHGEF17 (Figure 1B).6 The ARHGEF17 protein is a Rho guanine nucleotide exchange factor involved in cellular signaling.7 The fusion between the MLL and the ARHGEF17 genes occurred in introns 12 and 1, respectively. The reciprocal allele was isolated as well and fused ARHGEF17 intron 1 with MLL intron 12. The particular chimeric transcript leads to an in-frame fusion gene that expresses the corresponding fusion RNA (Figure 1C).
To discriminate between a rearrangement that already existed at diagnosis at a low level from a secondary one, molecular analysis of the chromosomal breakpoint region was performed in the diagnostic material. However, detection of the MLL-ARHGEF17 fusion gene sequence by using specific primers failed, indicating the appearance of a secondary, potentially treatment-induced rearrangement.
To further illuminate the biology of our observation, we precisely analyzed the morphology of those cells carrying the MLL-ARHGEF17 fusion gene 30 months after initial detection of the rearrangement (Figure 1D, Table 1).8 The novel MLL rearrangement could only be detected in cells within the myeloid lineage. Remarkably, all cell types of the myeloid lineage, from promyelocytes to differentiated polymorphonuclear neutrophils, were affected by the novel fusion gene, highlighting 2 conclusions: first, the MLL-ARHGEF17 rearrangement is an early clonal event in myelopoiesis, and second, the chimeric protein does not lead to a block of the myeloid differentiation.
Our data suggest that neither the MLL-ARHGEF17 nor the ARHGEF17-MLL gene fusion result in oncogenic dysregulation of cell growth. This is supported by the observation that the number of cells carrying the MLL rearrangement eventually started to decrease in the course of time. Nevertheless, this conclusion must be drawn very carefully, since the follow-up time of the patient is relatively short and we cannot exclude that MLL-ARHGEF17 and/or ARHGEF17-MLL contributes to leukemogenesis in combination with further additional genetic events. However, to our knowledge, this is the first report of an MLL rearrangement that results in a clonal population of cells but lacks leukemogenic behavior.
- Correspondence: Beat W. Schäfer, Department of Oncology, University Children's Hospital Zurich, Steinwiesstrasse 75, CH-8032 Zurich; e-mail: .
Supported by a grant from the Krebsliga of the Kanton Zurich and the Wilhelm-Sander-Stiftung.
- Copyright © 2005 by The American Society of Hematology