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CORRESPONDENCE MLL (also known as ALL1, HTRX,
or HRX) gene translocations are among the most common
chromosomal abnormalities in both B-lineage acute lymphoblastic
leukemia (B-ALL) and acute myeloid leukemia (AML). This MLL
involvement means that these leukemias constitute a distinct
disease1 with a particularly poor prognosis, which needs to
be more easily identified and better characterized if therapeutic
regimens are to be improved. MLL gene rearrangements have
been sporadically reported in acute lymphoblastic T-cell leukemia
(T-ALL),2,3 but the incidence of MLL
involvement in T-ALL could be consistently underestimated because
MLL rearrangements would seem to be due to translocations
that are difficult to detect by classic cytogenetic methods. Studying
the MLL gene could lead to the identification of a new group
of T-ALL, especially if this group also turned out to have a poor
clinical outcome. Here we present evidence that the MLL gene
could be in fact involved in more than 8% of adult T-ALL. We looked for MLL abnormalities in bone marrow samples from
47 adults and 34 children with unselected T-ALL. Immunophenotyping and
the assignment of the leukemias to the T lineage were based on the
classification of the European Group for the Immunological characterization of Leukemias. No correlation was observed between the
maturation of T-ALL and the involvement of the MLL gene. All the patients were screened by Southern blot analysis with various probes encompassing exon 3 to exon 22 of the
MLL gene, and also, where possible, by fluorescence in situ
hybridization (FISH). None of the children showed MLL
involvement, but in 4 adults a rearranged MLL gene was found
by at least 2 different methods: Southern blot analysis (Figure
1), reverse transcriptase-polymerase chain reaction (RT-PCR), and/or FISH analysis. Southern blot analysis showed that another adult (P5) had rearranged bands corresponding in
size to the site-specific DNA cleavage induced by the topoisomerase II
inhibitors that have been found in the MLL
gene.4 This result was further strengthened by the
fact that FISH analysis in this case revealed no abnormalities.
Moreover, Southern blot analysis of the P5 relapse sample did not
reveal the rearranged bands observed at diagnosis, strongly suggesting
that the MLL gene is not implicated in the T-ALL of this
patient.
The relevant clinical and biological data for the patients with
MLL involvement are given in Table
1. An interesting common feature was
that, in 3 of the 4 cases (P1, P2, P3), the breakpoint occurred outside
of the breakpoint cluster region (bcr) commonly involved in
MLL translocations,5 which may in part account for the fact that the incidence of MLL rearrangement has up
to now been underestimated in T-ALL. In P1, the breakpoint was located upstream from the usual MLL bcr (between exons 4c and 5),
and the fusion partner was the AF10 gene. In P2 and P3, the
breakpoint was located downstream from the usual MLL bcr,
between exons 20 and 21 and exons 18 and 19, respectively. Only in P4
the breakpoint occurred in the usual MLL bcr (between exon 6 and exon 7). With P2, P3, and P4, the MLL gene fused
with the AF6q27 gene. As with all the other 11q23
translocations so far investigated, an RT-PCR on leukemic cells from
P1, P2, P3, and P4 revealed an in-frame fusion transcript encoding the
amino-terminus of MLL and the carboxy-terminus of either AF10 (P1) or
AF6q27 (P2, P3, and P4). The fusion occurred at breakpoints already
described for the partner genes AF10 and AF6q27.6,7 It will be noted that the
contribution of the MLL protein to the fusion product was larger for P2
and P3 than in other cases described to date. It included, in
particular, the major part of the Drosophila trithorax
zinc-fingers domain of the MLL protein.8 The deletion of
the exon 8 of the MLL gene observed in some cases of
T-ALL9 was not found by RT-PCR on leukemic cells from the 5 rearranged cases (P1 to P5). P1 and P2 achieved complete remission (CR)
after 2 courses of induction chemotherapy, and they received allogenic
bone marrow transplants as consolidation therapy. They were
still alive 7 years and 3 years, respectively, after transplantation.
P3, P4, and P5 achieved CR after intensive standard chemotherapy but
relapsed a few months later and died. These observations suggest that
where there is MLL involvement, T-ALL, like other forms of
leukemia, responds particularly poorly to standard therapies.
To our knowledge, this is the first study of MLL abnormalities in a series of cases of T-ALL. Our findings, like those of previous studies on B-ALL and AML, suggest that the involvement of the MLL gene in adults T-ALL is recurrent, with an incidence of more than 8%. In view of these results and the fact that lymphoblastic leukemia with MLL translocation seems to constitute a distinct disease with a poor prognosis, we would recommend that adults with T-ALL be screened by FISH analysis for MLL abnormalities.
Sandrine Hayette, Isabelle Tigaud, Véronique Maguer-Satta, Laurent Bartholin, Xavier Thomas, Christiane Charrin, Mylène Gadoux, Jean-Pierre Magaud, and Ruth Rimokh
References 1. Armstrong SA, Staunton JE, Silverman LB, et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nature Genet. 2002;30:41-47[CrossRef][Medline] [Order article via Infotrieve]. 2. McCabe NR, Kipiniak M, Kobayashi H, et al. DNA rearrangements and altered transcripts of the MLL gene in a human T-ALL cell line Karpas-45 with a t(X;11)(q13;q23) translocation. Genes Chromosom Cancer. 1994;9:221-224[Medline] [Order article via Infotrieve]. 3. Chervinsky DS, Sait SNJ, Nowak NJ, Shows TB, Aplan PD. Complex MLL rearrangement in a patient with T-cell acute lymphoblastic leukemia. Genes Chromosom Cancer. 1995;14:76-84[Medline] [Order article via Infotrieve]. 4. Andersen MK, Christiansen DH, Jensen BA, Ernst P, Hauge G, Pedersen-Bjergaard J. Therapy-related acute lymphoblastic leukaemia with MLL rearrangements following DNA topoisomerase II inhibitors an increasing problem; report on two new cases and review of the literature since 1992. Br J Haematol. 2001;114:539-543[CrossRef][Medline] [Order article via Infotrieve]. 5. Gu Y, Alder H, Nakamura T, et al. Sequence analysis of the breakpoint cluster region in the ALL-1 gene involved in acute leukemia. Cancer Res. 1994;54:2327-2330. 6. Hjorth-Sorensen B, Pallisgaard N, Gronholm M, Hokland P, Clausen N, Jorgensen P. A novel MLL-AF10 fusion mRNA variant in a patient with acute myeloid leukemia detected by a new asymmetric reverse transcription PCR method. Leukemia. 1997;11:1588-1593[CrossRef][Medline] [Order article via Infotrieve].
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Prasad R, Gu Y, Alder H, et al.
Cloning of the ALL-1 fusion partner, the AF-6 gene, involved in acute myeloid leukemias with the t(6;11) chromosome translocation.
Cancer Res.
1993;53:5624-5628 8. Tkachuk DC, Kohler S, Cleary ML. Involvement of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell. 1992;71:691-700[CrossRef][Medline] [Order article via Infotrieve].
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Lochner K, Siegler G, Fuhrer M, et al.
A specific deletion in the breakpoint cluster region of the ALL-1 gene is associated with acute lymphoblastic T-cell leukemias.
Cancer Res.
1996;56:2171-2177   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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