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323
Scientific Comments
Rev Bras Hematol Hemoter. 2012;34(5):323-33
BCR-ABL rearrangement and HLA antigens: a possible link to leukemia pathogenesis
and immunotherapy
The translocation, t(9;22)(q34;q11), giving rise to the Philadelphia chromosome (Ph),
is observed in approximately 30% of acute lymphoblastic leukemia (ALL) and in virtually
all chronic myeloid leukemia (CML) patients, where it represents the diagnostic molecular
hallmark.
The reciprocal rearrangement joins the 5’ sequence of the breakpoint cluster region gene
(
BCR
) at 22q11 to the 3’ sequence of the c-abl oncogene 1 (
ABL1
) at 9q34, generating the
fusion gene
BCR/ABL1
.
Breakpoints in
ABL1
generally involve exon 2 (a2). Breakpoints in
BCR
occur in the
major breakpoint cluster region (
M-BCR
) in the great majority of CML patients and in the
minor breakpoint cluster region (
m-BCR
) in the bulk of subjects with Ph-positive ALL. Breaks
occurring in
M-BCR
juxtapose exon 13 or 14 to
ABL1
, resulting in the fusion transcripts
e13a2 (also designated b2a2) and e14a2 (also designated b3a2), respectively. Either
BCR/ABL
RNAmessengers translate in a chimeric oncoprotein with molecular weight of 210 kDa (p210
BCR-ABL
) which harbors constitutive tyrosine kinase activity driving the growth advantage of
the leukemic cell clone. Breaks in
m-BCR
bring together
BCR
exon 1 and
ABL1
, yielding a
smaller fusion transcript, e1a2, which codes for a 190 kDa chimeric oncoprotein (p190
BCR-ABL
)
with more transforming potential than p210
BCR-ABL
(1)
.
The junctional regions of p210
BCR-ABL
and p190
BCR-ABL
display a unique amino
acid sequence that is not found in any normal protein. Therefore, because the translated
BCR-ABL product is expressed only in leukemic cells and not in normal cells, the chimeric
peptides encompassing the e13a2, e14a2 or e1a2 breakpoints may act as potential targets for
specific T lymphocyte-mediated immune response against CML and ALL tumor cells.
However, T lymphocytes can recognize and can be stimulated to proliferate and to
perform the function of leukemia cell killing only if the processed chimeric antigens are
assembled at the cell surface in association with major histocompatibility complex (MHC)
class I and II molecules.
Several
in vitro
experiments indicate an association between BCR-ABL fusion products
and MHC alleles. In particular, different purified class I MHC molecules have been described
to bind strongly to peptides spanning the BCR-ABL e14a2 junction, including human
leukocyte antigen (HLA) A3 and B8 class I molecules.
Moreover, mass spectrometry studies demonstrated that e14a2 peptides are presented
on the cell surface of primary CML cells by HLA-A3 molecules. The results suggest that
determined BCR-ABL junctional peptides may preferentially bind to certain HLA alleles
thereby supporting the potential of these antigens as targets for class I HLA restricted T
lymphocyte cytotoxicity. On the other hand, an efficacious immune response may confer to
the individuals carrying these particular HLA alleles an advantage in fighting the leukemia.
Indeed, additional
in vitro
studies, in which exogenous cytokines substituting for CD4
+
lymphocyte helper function were used, have shown that these BCR-ABL peptides appear to
be immunogenic since they can elicit specific class I, HLA-restricted cytotoxic T lymphocyte
(CTL) responses in normal donors and CML patients. The findings demonstrate that patients
with CML have the
in vitro
capacity to respond to their own individual cancer cells and that
CML cells are competent in processing and presenting endogenous immunogenic e14a2
peptides in the context of class I HLA
(2)
.
Although less is known about the association of e14a2 BCR-ABL peptides with HLA
class II molecules, support for the immunogenicity of these antigens has been accumulating.
It has been demonstrated that it is possible to establish CD4
+
T-lymphocyte cell lines restricted
for HLA-DRB1*0401 presenting e14a2-derived peptides from healthy subjects and that these
cells showed a proliferative response to HLA-DRB1*0401-bearing e14a2-positive CML blasts.
On the other hand, these CD4
+
T-lymphocyte cell lines did not respond to HLA-DRB1*0401-
bearing e14a2-negative cells or HLA-DRB1*0401-negative e14a2-type CML blasts.
In another study, e14a2-derived peptides and HLA-DRB1*0901-restricted CD4
+
T-lymphocyte clones were established and their effect on CML cell growth was investigated.
Marina Giunta
1
Carlo Pucillo
2
1
Division of Hematology and Bone Marrow
Transplantation, Azienda Ospedaliero-
Universitaria di Udine – AOUD, Udine, Italy
2
Department of Medical and Biological
Sciences, University of Udine, Udine, Italy
Conflict-of-interest disclosure:
The authors declare no competing financial
interest
Submitted: 9/25/2012
Accepted: 9/27/2012
Corresponding author:
Carlo Pucillo
Lab of Immunology
Department of Medical and Biological Science
University of Udine
P.le M. Kolbe. 4
33100 Udine - Italy
Phone: +39 0432 494340
carlo.pucillo@uniud.it
www.rbhh.org or www.scielo.br/rbhh
DOI: 10.5581/1516-8484.20120082