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324
Scientific Comments
Rev Bras Hematol Hemoter. 2012;34(5):323-33
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The number of HLA-DRB1*0901-positive e14a2, but not those
of e13a2-positive or HLA-DRB1*0901-negative CML cell
colonies appeared to increase when CML cells were cultured with
e14a2-specific CD4
+
T lymphocyte clones.
The effect of e14a2-specific CD4
+
T lymphocyte clones on
e14a2-positive CML cell growth was inhibited by the addition of
anti-HLA-DR monoclonal antibodies. These data suggest that the
BCR-ABL chimeric protein is processed naturally in CML cells
and is recognized by BCR-ABL-specific CD4
+
T lymphocytes in
the context of HLA class II molecules.
To verify this possibility, the ability of dendritic cells (DCs)
derived from monocytes of CML patients to present endogenous
BCR-ABL chimeric peptides to CD4
+
T lymphocytes was
investigated. The results showed that CML-derived mature DCs
can process and present the endogenous BCR-ABL chimeric
protein to BCR-ABL peptide-specific CD4
+
T lymphocyte clones
in an HLA class II-restricted manner.
However, the sparse available data suggest that CD4
+
T
lymphocyte responses to BCR-ABL may be hindered in CML
patients compared to healthy individuals. Indeed, e14a2 peptides
are able to evoke a CD4
+
T lymphocyte response in normal subjects,
but cannot elicit specific clones from CML peripheral blood.
Much fewer data are obtainable for e13a2 junctional peptides
that are shown to bind at low affinity to B8 and A11 MHC class
I molecules and to yield T cell proliferative responses in a HLA-
DR2a restricted fashion only after repetitive stimulation.
Other scientific studies report analyses of the association
between particular HLA alleles and different types of BCR-ABL
fusion proteins at a population level, assuming that a negative
association of a particular BCR-ABL product with specific HLA
alleles suggests that these alleles play a critical role in presenting
peptides derived from the chimeric proteins and in eliciting a
successful T lymphocyte cytotoxic response
(3)
. In this perspective,
even if it is well known that different populations show different
HLA haplotype frequencies, the findings of Carvalho et al.
(4)
,
trying to unravel the issue of the association of HLAmolecules with
BCR-ABL peptides inside the Brazilian population, have the major
advantage of raising novel interests about the immune pathogenesis
of CML and the CML immune-mediated therapies. In fact, the
Carvalho et al. report indicates that BCR-ABL peptides may be
presented by different HLA molecules, which inside the specific
CML population may elicit a productive (negative association) or
ineffective (positive association) binding to leukemic proteins, in
comparison with the healthy population. Carvalho et al. showed a
positive association between HLA-A25 and HLA-B18 as well as
a negative association between HLA-A68 and e13a2 transcripts,
whereas they reported a positive association betweenHLA-B40 and
HLA-DRB1*3 with e14a2 transcripts
(4)
. On the basis of positive/
negative associations, it has been assumed that HLA-restricted T
lymphocyte cytotoxicity accomplishes an immunosurveillance role
in the pathogenesis of BCR-ABL leukemias.
In this regard, beside the aforementioned demonstration
of the immunogenicity of the peptides spanning the fusion
region of the chimeric proteins presented in the context of MHC
class I and II, several other observations provide coincidental
evidence for the existence and efficacy of immune reactions in
CML patients. For instance, it is well known that BCR-ABL
mRNAs have been detected in normal individuals and that
both CTL and CD4
+
proliferative responses against BCR-ABL
can be elicited in normal subjects suggesting the importance of
the immune response in controlling and/or eliminating BCR-
ABL positive leukemic clones. Even if we do not understand
the precise mechanisms of immune escape by the BCR-ABL
leukemic clone, causing the clinical emergence of the disease,
further proof of an immunologic component in the eradication
of leukemia cells comes from the demonstration that CML
may respond to immune-mediated therapies, including stem
cell transplantation, donor lymphocyte infusion and interferon
alpha administration.
This evidence indicates that under
in vivo
circumstances,
some, but apparently not always entirely efficient, immune
responses against leukemic cells do occur. Hence it may be
possible to gain durable remissions by boosting this immunity
with vaccination. In animal models, immunization with BCR-ABL
specific peptides can raise an antiserum reacting specifically with the
native p210
BCR-ABL
in CML cell lines and results from small-scale
clinical trials using vaccines based on the p210
BCR-ABL
chimeric
protein obtained beneficial effects in some patients. These findings
suggest that immunotherapeutic approaches may supplement the
current targeted therapies with tyrosine kinase inhibitors and may
be important to attain a definitive cure.
Clinical effects of BCR-ABL peptide vaccination associated
with imatinib have already been demonstrated in patients with
persistent residual disease and vaccination with BCR-ABL
junctional peptides might improve the reduction of
BCR-ABL
mRNAs in patients who had previously received imatinib for
more than 12 months.
Analyses ofHLAassociationwithdifferent BCR-ABLpeptides
may have therefore diagnostic and prognostic significance and
may advance our knowledge about strategies of BCR-ABL
immunization.
References
1. De Braekeleer E, Douet-Guilbert N, Rowe D, Bown N, Morel F, Berthou
C, et al. ABL1 fusion genes in hematological malignancies: a review. Eur
J Haematol. 2011;86(1):361-71
2. Clark RE. Immunotherapeutic strategies in chronic myeloid leukemia.
Curr Hematol Malig Rep. 2007;2(2):89-94
3. Mundhada S, Luthra R, Cano P. Association of HLA Class I and Class II
genes with bcr-abl transcripts in leukemia patients with t(9;22) (q34;q11).
BMC Cancer. 2004;4:25-32
4. Carvalho DL, Barbosa CD, Carvalho AL, Beck ST. Association of
HLA antigens and BCR-ABL transcripts in leukemia patients with the
Philadelphia chromosome. Rev Bras Hematol Hemoter. 2012;34(4):280-4.