MLL rearrangements in haematological malignancies: lessons from clinical and biological studies

Since the identi®cation of the Philadelphia chromosome almost 40 years ago, the study of speci®c chromosomal alterations in human cancer has had a major impact on the diagnosis of, and choice of treatment for, patients with haematological and other malignancies (Heim & Mitelman, 1995; Look, 1997). Karyotype analysis to identify chromosomal rearrangements is now a routine part of the diagnostic work-up for newly diagnosed and relapsed leukaemia patients. Due to years of correlative studies, many leukaemia-speci®c rearrangements can be used quite accurately for risk strati®cation and, in turn, to choose appropriate therapy. This paradigm has been demonstrated in paediatric acute lymphoblastic leukaemia (ALL) (reviewed by Rubnitz & Crist, 1997). For example, ALL patients with the t(1;19) translocation were initially found to be at higher risk of treatment failure. Treatment of these patients with more aggressive combinations of chemotherapy has resulted in long-term cure rates comparable to those of children with standard-risk ALL. In addition to serving as diagnostic and prognostic markers, recurring rearrangements are providing intriguing clues about the molecular events underlying leukaemogenesis. The cloning and functional analysis of genes whose structure or expression is altered as a result of chromosomal rearrangements is yielding unprecedented insights into the mechanism(s) of neoplastic transformation (Look, 1997). Among cancer-related chromosomal aberrations that are shedding new light on the origins of haematological malignancies, a family of rearrangements involving the MLL (Myeloid/Lymphoid Leukaemia or Mixed Lineage Leukaemia) gene on chromosome 11, band q23 is proving to be a fertile area of investigation. MLL rearrangements include non-constitutional or acquired deletions, duplications, inversions and reciprocal translocations at 11q23. As a group, these rearrangements account for 5±10% of acquired chromosomal rearrangements in children and adults with ALL, acute myeloblastic leukaemia (AML), poorly differentiated or biphenotypic leukaemias and myelodysplastic syndromes (MDS) (Heim & Mitelman, 1995). Strikingly, the majority of acute leukaemias in neonates and infants (children <1 year of age), as well as secondary or treatment-related leukaemias, have clonal rearrangements involving 11q23 (Chen et al, 1993; Reaman et al, 1985; Spier et al, 1984; Rubnitz et al, 1994a). Independent of their association with other high-risk features at presentation, 11q23 rearrangements are strongly predictive of poor clinical outcome. Despite the use of more aggressive induction regimens and stem cell transplant in ®rst remission, patients with 11q23 rearrangements continue to have poor long-term survival (Rubnitz et al, 1994a; Pui et al, 1991, 1994). Thus, in addition to their role in the neoplastic transformation of haemopoietic progenitors, 11q23 rearrangements may also affect the response of leukaemic blasts to chemotherapy. In this review we discuss some of the recent advances from clinical as well as biological studies of these rearrangements, with an emphasis on the possible mechanisms of leukaemic transformation by MLL fusion proteins.