TY  - JOUR
AU  - Kempter, Tamara
AU  - Richter-Pechańska, Paulina
AU  - Michel, Katarzyna
AU  - Rausch, Tobias
AU  - Erarslan-Uysal, Büşra
AU  - Eckert, Cornelia
AU  - Zimmermann, Martin
AU  - Stanulla, Martin
AU  - Schrappe, Martin
AU  - Cario, Gunnar
AU  - Köhrer, Stefan
AU  - Attarbaschi, Andishe
AU  - Korbel, Jan O
AU  - Kunz, Joachim B
AU  - Kulozik, Andreas
TI  - Subclonal TP53 and KRAS variants combined with poor treatment response identify ultrahigh-risk pediatric patients with T-ALL.
JO  - Blood advances
VL  - 9
IS  - 6
SN  - 2473-9529
CY  - Washington, DC
PB  - American Society of Hematology
M1  - DKFZ-2025-00572
SP  - 1267 - 1279
PY  - 2025
N1  - #LA:A400#
AB  - Variations in the TP53 and KRAS genes indicate a particularly adverse prognosis in relapsed pediatric T-cell acute lymphoblastic leukemia (T-ALL). We hypothesized that these variations might be subclonally present at disease onset and contribute to relapse risk. To test this, we examined 2 cohorts of children diagnosed with T-ALL: cohort 1 with 81 patients who relapsed and 79 who matched nonrelapsing controls, and cohort 2 with 226 consecutive patients, 30 of whom relapsed. In cohort 1, targeted sequencing revealed TP53 clonal and subclonal variants in 6 of 81 relapsing patients but none in the nonrelapsing group (P = .014). KRAS alterations were found in 9 of 81 relapsing patients compared with 2 of 79 nonrelapsing patients (P = .032). Survival analysis showed that none of the relapsed patients with TP53 and/or KRAS alterations survived, whereas 19 of 67 relapsed patients without such variants did, with a minimum follow-up time of 3 years (P = .023). In cohort 2, none of the relapsing patients but 10 of 196 nonrelapsing patients carried TP53 or KRAS variants, indicating that mutation status alone does not predict poor prognosis. All 10 nonrelapsing patients with mutations had a favorable early treatment response. Among the total cohort of 386 patients, 188 showed poor treatment response, of whom 69 relapsed. Of these poor responders, 9 harbored TP53 or KRAS variants. In conclusion, subclonal TP53 and KRAS alterations identified at the time of initial diagnosis, along with a poor treatment response, characterize a subset of children with T-ALL who face a dismal prognosis and who may benefit from alternative treatment approaches.
KW  - Humans
KW  - Tumor Suppressor Protein p53: genetics
KW  - Proto-Oncogene Proteins p21(ras): genetics
KW  - Child
KW  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma: genetics
KW  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma: mortality
KW  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma: diagnosis
KW  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma: therapy
KW  - Male
KW  - Female
KW  - Child, Preschool
KW  - Prognosis
KW  - Adolescent
KW  - Infant
KW  - Mutation
KW  - Treatment Outcome
KW  - Tumor Suppressor Protein p53 (NLM Chemicals)
KW  - Proto-Oncogene Proteins p21(ras) (NLM Chemicals)
KW  - KRAS protein, human (NLM Chemicals)
KW  - TP53 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39808796
DO  - DOI:10.1182/bloodadvances.2024014209
UR  - https://inrepo02.dkfz.de/record/299835
ER  -