ALL1 gene alterations in acute leukemia: biological and clinical aspects

The ALL1 gene, also referred to as MLL, HRX or Htrx1, is interrupted in the vast majority of translocations involving the chromosome band 11q23. Alterations in this gene are reported in approximately 5-10% of acute leukemias (AL) and characterize different leukemic subtypes such as infant (< 12 months of age) AL, topoisomerase II inhibitors-related (TR) AL and a small subset of de novo AML and ALL. Distinguishing features of ALL1 alterations include the striking heterogeneity of its recombinations, i.e., more than 30 chromosome partners have been described in ALL1 rearrangements, and the lack of association with a definite lineage. The objective of this article is to review the biological and structural properties of ALL1 gene and its various fusion proteins, and to discuss the clinical relevance of these lesions with special emphasis on their role in molecular diagnosis and monitoring of minimal residual disease.

The material examined in the present review includes data published by the authors in this field, articles and abstracts published in journals covered by the Science Citation Index and Medline, as well as some more recent personal unpublished observations.

The ALL1 gene spans approximately 90 kb of DNA in length, and consists of 36 exons, ranging in size from 65 bp to 4249 bp. ALL1 codifies for a major transcript of approximately or equal to 15 kb. It encodes a protein of more than 3910 amino acids, containing three regions sharing sequence homology with the Drosophila trithorax gene. These homologies suggest that ALL1 is a transcription factor controlling development and/or differentiation of human cells. To date, twelve ALL1 partner genes have been characterized which are involved in the following translocations: t(4;11), t(9;11), t(6;11), t(11;19), t(1;11) t(10;11), t(11;16), t(11;17) and t(X;11). Since all these genes do not share relevant homologies among each other, their putative role in ALL1 activation still remains to be clarified. The analysis of ALL1 breakpoint cluster region (bcr) shows that several DNA motifs implicated in illegitimate recombination events are located within the bcr. Thus, mapping of breakpoints in the different subtypes of ALL1 +ve leukemia may help in understanding the events leading to translocations in human ALs. In this respect, data on ALL1 breakpoint localization suggest that similar pathogenetic mechanisms may underlie infant and TR AL and that these events might differ from those occurring in de novo AL. The availability of this molecular marker provides a new tool for diagnostic purposes and characterization of ALs and for monitoring of minimal residual disease. To date, the prognostic value of ALL1 rearrangements has been clearly demonstrated for infant ALs only, whereas the clinical relevance of ALL1 rearrangements in the other leukemic subtypes needs further evaluation by future prospective studies on a larger number of patients homogeneously treated. As concerning studies on minimal residual disease, data on PCR monitoring of the ALL1/AF4 fusion transcript, resulting from the t(4;11) translocation, show the clinical relevance of this molecular test in predicting outcome and, as a consequence, in designing individual post-remission therapies.

It is expected that future studies will provide more detailed information regarding either the normal ALL1 function and/or the leukemogenic effect of ALL1 alterations, together with a better definition of the prognostic relevance of the hybrid proteins formed by this gene at diagnosis and during remission of disease.