Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.5.1.1 (
asparaginase
)
2,695
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is associated with a high frequency of copy number alterations (CNAs) in IKZF1, EBF1,
PAX5
, CDKN2A/B, RB1, BTG1, ETV6, and/or the PAR1 region (henceforth: B-cell development genes). We aimed to gain insight in the association between CNAs in these genes, clinical outcome parameters, and cellular drug resistance. 71% of newly diagnosed pediatric BCP-ALL cases harbored one or more CNAs in these B-cell development genes. The distribution and clinical relevance of these CNAs was highly subtype-dependent. In the DCOG-ALL10 cohort, only loss of IKZF1 associated as single marker with unfavorable outcome parameters and cellular drug resistance. Prednisolone resistance was observed in IKZF1-deleted primary high hyperdiploid cells (~1500-fold), while thiopurine resistance was detected in IKZF1-deleted primary BCR-ABL1-like and non-BCR-ABL1-like B-other cells (~2.7-fold). The previously described risk stratification classifiers, i.e. IKZF1
plus
and integrated cytogenetic and CNA classification, both predicted unfavorable outcome in the DCOG-ALL10 cohort, and associated with ex vivo drug cellular resistance to thiopurines, or
L-asparaginase
and thiopurines, respectively. This resistance could be attributed to overrepresentation of BCR-ABL1-like cases in these risk groups. Taken together, our data indicate that the prognostic value of CNAs in B-cell development genes is linked to subtype-related drug responses.
...
PMID:Copy number alterations in B-cell development genes, drug resistance, and clinical outcome in pediatric B-cell precursor acute lymphoblastic leukemia. 3087 17
Resistance to
L-asparaginase
(L-asp) is a major contributor to poor treatment outcomes of several subtypes of childhood B cell precursor acute lymphoblastic leukemia (BCP-ALL). Asparagine synthetase (
ASNS
), legumain (
LGMN
) and cathepsin B (
CTSB
) serve a key role in L-asp resistance. The association between genetic subtypes of BCP-ALL and the expression of
ASNS, LGMN
and
CTSB
may elucidate the mechanisms of treatment failure. Bone marrow samples of 52 children newly diagnosed with BCP-ALL were screened for major genetic abnormalities and
ASNS, LGMN
and
CTSB
gene expression levels. The cohort was further divided into groups corresponding to the key genetic aberrations occurring in BCP-ALL: Breakpoint cluster region and Abelson murine leukemia viral oncogene homolog 1 fusion; hyperdiploidy, hypodiploidy, ETS variant 6 and runt-related transcription factor 1 fusion and other BCP-ALL with no primary genetic aberration identified. A subgroup analysis based on the differences in copy number variations demonstrated a significant increase of
ASNS, LGMN
and
CTSB
median expression in other BCP-ALL cases with
paired box 5
(
PAX5
) deletion (P=0.0117; P=0.0036; P<0.0001, respectively) compared with those with wild-type
PAX5
. Patients with high
ASNS
expression exhibited longer relapse-free survival (RFS) compared with those with low
ASNS
levels (P=0.0315; HR, 0.19; 95% CI, 0.04-0.86); the 5-year RFS for patients in the high
ASNS
expression group was 90.15% (95% CI, 87.90-92.40%). Despite the impact on
ASNS, LGMN
and
CTSB
expression,
PAX5
deletion did not influence RFS in the other BCP-ALL group (P=0.6839). Therefore, the results of the present study revealed high levels of
ASNS, LGMN
and
CTSB
expression in the other BCP-ALL group with concomitant
PAX5
deletion and no subsequent deterioration in 5-year RFS. High
ASNS
expression level, as a single factor, was strongly associated with an improved outcome.
...
PMID:Gene expression of
ASNS, LGMN
and
CTSB
is elevated in a subgroup of childhood BCP-ALL with
PAX5
deletion. 3180 94
