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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INTRODUCTION
Acute lymphoblastic leukemia (ALL) is the most
prevalent form of cancer among children, comprising 25%
of all childhood malignancies, with a consistently increas-
ing incidence rate over the years [1, 2]. It arises following
the clonal proliferation of immature B and/or T lymphoid
cells, with around 80% of the cases being of B lineage
origin [3, 4]. The most common initial genetic lesions
are chromosomal loss (hypodiploidy), gain (hyperdip-
loidy), or fusion genes, leading to a pre-leukemic clone.
A subsequent second hit, either a copy number alteration
(CNA) or single nucleotide variant (SNV), is believed to
be the cause of lymphoid arrest and the development of
symptomatic disease [4, 5].
Conventional (karyotyping, fluorescence in situ hy-
bridization - FISH) and molecular (reverse transcription
quantitative polymerase chain reaction - qRT-PCR, multi-
plex ligation-dependent probe amplification - MLPA) tech-niques are routinely used for the identification of numerical
and structural chromosomal abnormalities, allowing for
the detection of several disease subtypes with different
prognostic and therapeutic associations [3, 5, 6]. Among
these, high-hyperdiploidy is the most common subtype
in childhood B-ALL (25-30%), which is associated with
favorable prognosis [6-8]. The structural chromosomal
abnormalities involve genes that regulate hematopoiesis
and lymphoid development (RUNX1, ETV6), activate on-
cogenes (MYC), or constitutively activate tyrosine kinases
(ABL1). In particular, recurring translocations leading to
different subtypes in B-ALL include t(12;21)(p13;q22) en-
coding ETV6::RUNX1 associated with favorable progno-
sis, t(1;19)(q23;p13) encoding TCF3::PBX1 with interme-
diate prognosis, t(9;22)(q34;q11) encoding BCR::ABL1,
and rearrangements of MLL at 11q23 with different partner
genes, both associated with poor prognosis [7, 8]. More
recently, genomic profiling has led to the identification of
new abnormalities that are not detectable by conventional
methods, resulting in more than 20 disease subtypes [9, 10].
The risk classification at diagnosis of patients with
ALL varies among different treatment protocols, but in
general this includes the patient’s age, white blood cell
(WBC) count, and presence of specific disease subtypes. In
general, patients are classified as standard-risk if diagnosed
at the age 1-5, presenting a WBC count of < 20 x 10^9/L
and the absence of iAMP21, IKZF1 deletion or CRLF2
overexpression. The high-risk group includes patients
with either poor prednisolone response, hypodiploidy,
BCR::ABL1, TCF3::HLF or MLL::AFF1 subtypes, or any
other MLL rearrangement in patients younger than 1 year,
while all other patients are considered intermediate-risk.
Although the identification of disease subtypes conveying
prognostic significance along with minimal residual dis-
ease (MRD) assessment represent cornerstones for disease
stratification, approximately half of the relapses occur in
patients from standard-risk groups [11]. Additionally, it has
been shown that more than half of the relapse samples have
at least one genetic alteration originating either from the
leukemic or the pre-leukemic clone, potentially affecting
disease progression and therapy response [12,13]. Many of
these alterations affect transcription factors (ETV6, PAX5,
and IKZF1), epigenetic regulators (ATF7IP, SETD2, KM-
T2D, and CREBBP), cell cycle regulators (CDKN2A/B,
BTG1, and RB1), RAS pathway genes (KRAS, NRAS, and
PTPN11), and the tyrosine kinase FLT3 [14, 15]. Identi-
fication of the drivers of treatment failure is crucial for
detection of high-risk clones at the time of diagnosis, which
can also contribute to uncovering new therapeutic targets,
personalization of the treatment protocol and reduction
of the short- and long-term adverse effects of intensified
chemotherapy.
In this prospective observational national study, we
present the clinical variables, identify the most common
molecular biomarkers and the individual therapy response
(MRD) data, as well as their relation to the clinical status
in a cohort of 55 children with B-ALL. Additionally, we
conduct a more comprehensive analysis of the patients who
experienced disease relapse using whole exome sequenc-
ing to detect other alterations that may prove useful in
risk stratification and to potentially discover new altered
pathways that could be targeted therapeutically.
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