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000179973 1001_ $$aRichter-Pechańska, Paulina$$b0
000179973 245__ $$aPediatric T-ALL type-1 and type-2 relapses develop along distinct pathways of clonal evolution.
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000179973 500__ $$a#LA:B062# / 2022 Jul;36(7):1759-1768
000179973 520__ $$aThe mechanisms underlying T-ALL relapse remain essentially unknown. Multilevel-omics in 38 matched pairs of initial and relapsed T-ALL revealed 18 (47%) type-1 (defined by being derived from the major ancestral clone) and 20 (53%) type-2 relapses (derived from a minor ancestral clone). In both types of relapse, we observed known and novel drivers of multidrug resistance including MDR1 and MVP, NT5C2 and JAK-STAT activators. Patients with type-1 relapses were specifically characterized by IL7R upregulation. In remarkable contrast, type-2 relapses demonstrated (1) enrichment of constitutional cancer predisposition gene mutations, (2) divergent genetic and epigenetic remodeling, and (3) enrichment of somatic hypermutator phenotypes, related to BLM, BUB1B/PMS2 and TP53 mutations. T-ALLs that later progressed to type-2 relapses exhibited a complex subclonal architecture, unexpectedly, already at the time of initial diagnosis. Deconvolution analysis of ATAC-Seq profiles showed that T-ALLs later developing into type-1 relapses resembled a predominant immature thymic T-cell population, whereas T-ALLs developing into type-2 relapses resembled a mixture of normal T-cell precursors. In sum, our analyses revealed fundamentally different mechanisms driving either type-1 or type-2 T-ALL relapse and indicate that differential capacities of disease evolution are already inherent to the molecular setup of the initial leukemia.
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000179973 7001_ $$aKunz, Joachim B$$b1
000179973 7001_ $$00000-0001-5773-5620$$aRausch, Tobias$$b2
000179973 7001_ $$aErarslan-Uysal, Büşra$$b3
000179973 7001_ $$00000-0003-2890-3191$$aBornhauser, Beat$$b4
000179973 7001_ $$aFrismantas, Viktoras$$b5
000179973 7001_ $$0P:(DE-He78)45a6854ecf41ba2e65ca3ba0d560f14c$$aAssenov, Yassen$$b6
000179973 7001_ $$aZimmermann, Martin$$b7
000179973 7001_ $$aHappich, Margit$$b8
000179973 7001_ $$avon Knebel-Doeberitz, Caroline$$b9
000179973 7001_ $$avon Neuhoff, Nils$$b10
000179973 7001_ $$aKöhler, Rolf$$b11
000179973 7001_ $$00000-0002-3834-0727$$aStanulla, Martin$$b12
000179973 7001_ $$aSchrappe, Martin$$b13
000179973 7001_ $$aCario, Gunnar$$b14
000179973 7001_ $$aEscherich, Gabriele$$b15
000179973 7001_ $$00000-0001-6335-3274$$aKirschner-Schwabe, Renate$$b16
000179973 7001_ $$0P:(DE-He78)fd9d6272a48791a31f40a854585db572$$aEckert, Cornelia$$b17$$udkfz
000179973 7001_ $$aAvigad, Smadar$$b18
000179973 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan M$$b19$$udkfz
000179973 7001_ $$aMuckenthaler, Martina U$$b20
000179973 7001_ $$aBourquin, Jean-Pierre$$b21
000179973 7001_ $$aKorbel, Jan O$$b22
000179973 7001_ $$0P:(DE-He78)ca062b8db1ee864e03f0a92897728df3$$aKulozik, Andreas$$b23$$eLast author$$udkfz
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