Background and Objective. The ALL1 gene, also referred to as MLL, HRX
or Htrx1, is interrupted in the vast majority of translocations involv
ing the chromosome band 11q23. Alterations in this gene are reported i
n approximately 5-10% of acute leukemias (AL) and characterize differe
nt leukemic subtypes such as infant (< 12 months of age) AL, topoisome
rase II inhibitors-related (TR) AL and a small subset of de novo AML a
nd ALL. Distinguishing features of ALL1 alterations include the striki
ng heterogeneity of its recombinations, i.e. more than 30 chromosome p
artners have been described in ALL1 rearrangements, and the lack of as
sociation 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 thes
e lesions with special emphasis on their role in molecular diagnosis a
nd monitoring of minimal residual disease. Evidence and Information So
urces. The material examined in the present review includes data publi
shed by the authors in this field, articles and abstracts published in
journals covered by the Science Citation Index(R) and Medline(R), as
well as some more recent personal unpublished observations. State of t
he Art. 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 codi
fies for a major transcript of congruent to 15 kb. It encodes a protei
n of more than 3910 amino acids, containing three regions sharing sequ
ence homology with the Drosophila trithorax gene. These homologies sug
gest that ALL1 is a transcription factor controlling development and/o
r differentiation of human cells. To date, twelve ALL1 partner genes h
ave been characterized which are involved in the following translocati
ons: 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 homo
logies among each other, their putative role in ALL1 activation still
remains to be clarified. The analysis of ALL1 breakpoint cluster regio
n (bcr) shows that several DNA motifs implicated in illegitimate recom
bination events are located within the bcr. Thus, map ping of breakpoi
nts in the different subtypes of ALL1+ve leukemia may help in understa
nding the events leading to translocations in human ALs. In this respe
ct, data on ALL1 breakpoint localization suggest that similar pathogen
etic mechanisms may underlie infant and TR AL and that these events mi
ght differ from those occurring in de novo AL. The availability of thi
s molecular marker provides a new tool for diagnostic purposes and cha
racterization of ALs and for monitoring of minimal residual disease. T
o date, the prognostic value of ALL1 rearrangements has been clearly d
emonstrated for infant ALs only, whereas the clinical relevance of ALL
1 rearrangements in the other leukemic subtypes needs further evaluati
on by future prospective studies on a larger number of patients homoge
neously treated. As concerning studies on minimal residual disease, da
ta on PCR monitoring of the ALL1/AF4 fusion transcript, resulting from
the t(4;11) translocation, show the clinical relevance of this molecu
lar test in predicting outcome and, as a consequence, in designing ind
ividual post-remission therapies. Perspectives. It is expected that fu
ture studies will provide more detailed information regarding either t
he normal ALL1 function and/or the leukemogenic effect of ALL1 alterat
ions, together with a better definition of the prognostic relevance of
the hybrid proteins formed by this gene at diagnosis and during remis
sion of disease. (C) 1998, Ferrata Storti Foundation.