CREBBP IS A MAJOR PROGNOSTIC BIOMARKER FOR RELAPSE IN CHILDHOOD B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA: A NATIONAL STUDY OF UNSELECTED COHORT
Krstevska Bozhinovikj E1, Matevska-Geshkovska N1, Staninova Stojovska M1,
Gjorgievska E1, Jovanovska A2, Kocheva S2*, Dimovski A1,3*
*Corresponding Author: *Corresponding Authors: Prof. Aleksandar Dimovski MD PhD. Center for Biomolecular Pharmaceutical
Analyses, Faculty of Pharmacy, University Ss. Cyril and Methodius in Skopje, Mother Theresa 47, 1000
Skopje, N. Macedonia adimovski@ff.ukim.edu.mk; phone number: +38923119694 ext109;
Research Center for Genetic Engineering and Biotechnology “Georgi D. Efremov”, Macedonian Academy
of Sciences and Arts, Bul. Krste Misirkov 2, 1000, Skopje, N. Macedonia, a.dimovski@manu.edu.mk;
phone number: +38923235411
page: 5
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DISCUSSION
This study presents data from all pediatric patients
diagnosed with B-ALL in our country over a period of
six years. All patients were treated according to the ALL-
IC-BFM 2002 protocol, which was escalated to high-risk
protocol in eight patients. After a median follow-up of 46
months, five patients (9%) experienced disease relapse. In
general, the patients with relapse were diagnosed before
the age of 6; none presented with CNS infiltration at di-
agnosis, and the WBC count was slightly higher than 20 x
10^9/L in only one patient. Initial high-risk features (poor
prednisolone response and BCR::ABL1 hybrid transcript)
were detected in only two of the five patients with relapse.
These findings support the need for inclusion of new mo-
lecular biomarkers to help identify the high-risk clones at
diagnosis and redefine the stratification [6,21].
We identified the presence of alterations in the CREBBP
gene in 80% (4 out of 5) of the patients with relapse in our
cohort, all of which occurred in the HAT domain of the gene.
These alterations were found at the time of initial diagnosis
in 2 and at relapse in another 2 patients. Notably, none of the
specimens from patients in remission featured alterations in
this gene. The CREBBP gene has been recognized as one of
the most common relapse-enriched genes in ALL [22-24],
and its association with relapse is particularly evident in
the high-hyperdiploid subtype [10, 25]. Alterations in this
gene affect the response to one of the key components of
the treatment protocol, glucocorticoids, leading to a treat-
ment failure [22]. The mechanisms through which CREBBP
contribute to glucocorticoid resistance are considered to be
associated with its activity as a transcriptional co-activator,
which interacts with the glucocorticoid receptor (GR) and
potentially modulates its transcriptional activity. When glu-
cocorticoids bind to the GR, the receptor undergoes a con-
formational change allowing it to interact with co-activators
like CREBBP, which in turn can acetylate histones and
other chromatin regulators, promoting a more accessible
chromatin structure and facilitating gene transcription of
target genes involved in processes like apoptosis. Therefore,
alterations in this gene can lead to disruption of normal
cellular processes including transcriptional regulation, chro-
matin remodeling and apoptosis. Importantly, mutations
in the CREBBP gene also have a therapeutic significance,
as it has been found that different CREBBP inhibitors and
histone deacetylase inhibitors can alleviate chemotherapy
resistance and may become a successful approach for the
treatment of relapsed ALL [26].
We also detected alterations in several other genes
with potential prognostic value. These include deletions in
TP53 in two patients with relapse (in one of them relapse-
specific) which were infrequent in the rest of the patients,
and deletion in EBF1 gene in one patient with relapse which
was absent in the rest of the patients in our cohort. Previous
studies have also associated these alterations with disease
progression and reduced overall survival rates [3, 5, 22,
27, 28]. Furthermore, NRAS gene mutation was found at
relapse only, in one of the patients. Mutations in this gene
have been observed in high-risk ALL by others and have
been reported as important biomarkers for poor relapse-
free survival [23, 29, 30]. However, NRAS mutation was
also lost in the relapse clone in another patient from our
cohort, indicating its sub-clonal nature and uncertain role
in clonal chemoresistance. By contrast, deletions of IKZF1
and CDKN2A/2B genes, individually reported as high-risk
markers for disease progression and correlated with poor
outcome in several studies [31-34], were not found to inde-
pendently influence prognosis in our study. Their prognostic
significance has been further refined with the detection of the IKZF1plus profile [20] which, however, was not present in our
cohort. Additionally, the occurrence of the IKZF1 deletion
in the high-hyperdiploid subtype, which was also associated
with an increased relapse risk in a recent large prospective
study [10], was detected in one patient in our cohort, who
is still in remission after a follow-up of 46 months.
Concerning the evolutionary mechanisms of the
clones from diagnosis to relapse, we found that none of the
patients with relapse in our cohort experienced expansion
of a novel clonal population completely distinct from the
population present at diagnosis. Rather, in most of them
(4 out of 5), in addition to the same clonal rearrangement
and initiating genetic event (CNA, hybrid transcript), we
observed novel alterations at relapse that were not detected
in the primary clone/s. This either indicates that they were
present in minor sub-clones, not detectable with the applied
method, survived chemotherapy, and arose as dominant
clone/s due to the presence of chemotherapy resistance
mutations, or that they were acquired during chemotherapy
(treatment-induced) [13, 22]. However, the absence of
other alterations in three of these patients suggests that the
clonal evolution from an ancestral sub-clone was probably
the mechanism for relapse, which has also been described
as the most frequent event by others [13, 24, 35]. Only one
patient retained all the alterations within the diagnostic and
relapse clones, suggesting a linear evolution [35].
The strengths of this study are that it includes an
unselected cohort of pediatric patients with B-ALL who
were uniformly treated, and that it provides comprehen-
sive data for all patients along with detailed molecular
characterization for those with relapse. The limitations
of the study include the lack of complete knowledge of
the frequency of SNVs at diagnosis in patients without
relapse, the insufficient depth of the WES analysis to detect
mutations present in minor sub-clones (<10%), and the
relatively small patient cohort.
In conclusion, we identified that alterations in the epi-
genetic regulator CREBBP were the most frequent event
in the patients with relapse, either appearing at diagnosis
or being acquired at relapse. Screening for alterations in
this gene at the beginning, and/or at multiple time-points
during chemotherapy, could be incorporated into treatment
protocols, as they may contribute to the identification of
significant number of patients with predefined or acquired
chemoresistant clones. In addition, detection of deletions in
the TP53 and EBF1 genes in the CREBBP-negative patients
could further help identify patients at increased risk for re-
lapse. Finally, screening for clinically actionable alterations
in these and other pathways and genes (RAS, MMR genes),
could be of substantial significance for patients with re-
lapse in the coming years by offering a more individualized
targeted therapy or immunotherapy therapeutic approach.
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