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000299835 1001_ $$aKempter, Tamara$$b0
000299835 245__ $$aSubclonal TP53 and KRAS variants combined with poor treatment response identify ultrahigh-risk pediatric patients with T-ALL.
000299835 260__ $$aWashington, DC$$bAmerican Society of Hematology$$c2025
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000299835 520__ $$aVariations in the TP53 and KRAS genes indicate a particularly adverse prognosis in relapsed pediatric T-cell acute lymphoblastic leukemia (T-ALL). We hypothesized that these variations might be subclonally present at disease onset and contribute to relapse risk. To test this, we examined 2 cohorts of children diagnosed with T-ALL: cohort 1 with 81 patients who relapsed and 79 who matched nonrelapsing controls, and cohort 2 with 226 consecutive patients, 30 of whom relapsed. In cohort 1, targeted sequencing revealed TP53 clonal and subclonal variants in 6 of 81 relapsing patients but none in the nonrelapsing group (P = .014). KRAS alterations were found in 9 of 81 relapsing patients compared with 2 of 79 nonrelapsing patients (P = .032). Survival analysis showed that none of the relapsed patients with TP53 and/or KRAS alterations survived, whereas 19 of 67 relapsed patients without such variants did, with a minimum follow-up time of 3 years (P = .023). In cohort 2, none of the relapsing patients but 10 of 196 nonrelapsing patients carried TP53 or KRAS variants, indicating that mutation status alone does not predict poor prognosis. All 10 nonrelapsing patients with mutations had a favorable early treatment response. Among the total cohort of 386 patients, 188 showed poor treatment response, of whom 69 relapsed. Of these poor responders, 9 harbored TP53 or KRAS variants. In conclusion, subclonal TP53 and KRAS alterations identified at the time of initial diagnosis, along with a poor treatment response, characterize a subset of children with T-ALL who face a dismal prognosis and who may benefit from alternative treatment approaches.
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000299835 650_7 $$2NLM Chemicals$$aTumor Suppressor Protein p53
000299835 650_7 $$0EC 3.6.5.2$$2NLM Chemicals$$aProto-Oncogene Proteins p21(ras)
000299835 650_7 $$2NLM Chemicals$$aKRAS protein, human
000299835 650_7 $$2NLM Chemicals$$aTP53 protein, human
000299835 650_2 $$2MeSH$$aHumans
000299835 650_2 $$2MeSH$$aTumor Suppressor Protein p53: genetics
000299835 650_2 $$2MeSH$$aProto-Oncogene Proteins p21(ras): genetics
000299835 650_2 $$2MeSH$$aChild
000299835 650_2 $$2MeSH$$aPrecursor T-Cell Lymphoblastic Leukemia-Lymphoma: genetics
000299835 650_2 $$2MeSH$$aPrecursor T-Cell Lymphoblastic Leukemia-Lymphoma: mortality
000299835 650_2 $$2MeSH$$aPrecursor T-Cell Lymphoblastic Leukemia-Lymphoma: diagnosis
000299835 650_2 $$2MeSH$$aPrecursor T-Cell Lymphoblastic Leukemia-Lymphoma: therapy
000299835 650_2 $$2MeSH$$aMale
000299835 650_2 $$2MeSH$$aFemale
000299835 650_2 $$2MeSH$$aChild, Preschool
000299835 650_2 $$2MeSH$$aPrognosis
000299835 650_2 $$2MeSH$$aAdolescent
000299835 650_2 $$2MeSH$$aInfant
000299835 650_2 $$2MeSH$$aMutation
000299835 650_2 $$2MeSH$$aTreatment Outcome
000299835 7001_ $$aRichter-Pechańska, Paulina$$b1
000299835 7001_ $$aMichel, Katarzyna$$b2
000299835 7001_ $$aRausch, Tobias$$b3
000299835 7001_ $$aErarslan-Uysal, Büşra$$b4
000299835 7001_ $$aEckert, Cornelia$$b5
000299835 7001_ $$aZimmermann, Martin$$b6
000299835 7001_ $$aStanulla, Martin$$b7
000299835 7001_ $$aSchrappe, Martin$$b8
000299835 7001_ $$aCario, Gunnar$$b9
000299835 7001_ $$aKöhrer, Stefan$$b10
000299835 7001_ $$00000-0002-9285-6898$$aAttarbaschi, Andishe$$b11
000299835 7001_ $$aKorbel, Jan O$$b12
000299835 7001_ $$aKunz, Joachim B$$b13
000299835 7001_ $$0P:(DE-He78)ca062b8db1ee864e03f0a92897728df3$$aKulozik, Andreas$$b14$$eLast author$$udkfz
000299835 773__ $$0PERI:(DE-600)2876449-3$$a10.1182/bloodadvances.2024014209$$gVol. 9, no. 6, p. 1267 - 1279$$n6$$p1267 - 1279$$tBlood advances$$v9$$x2473-9529$$y2025
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