Journal Article

DKFZ-2022-01013

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Pediatric T-ALL type-1 and type-2 relapses develop along distinct pathways of clonal evolution.

Richter-Pechańska, P. ; Kunz, J. B. ; Rausch, T. ; Erarslan-Uysal, B. ; Bornhauser, B. ; Frismantas, V. ; Assenov, Y.DKFZ* ; Zimmermann, M. ; Happich, M. ; von Knebel-Doeberitz, C. ; von Neuhoff, N. ; Köhler, R. ; Stanulla, M. ; Schrappe, M. ; Cario, G. ; Escherich, G. ; Kirschner-Schwabe, R.DKFZ* ; Eckert, C.DKFZ* ; Avigad, S. ; Pfister, S. M.DKFZ* ; Muckenthaler, M. U. ; Bourquin, J.-P. ; Korbel, J. O. ; Kulozik, A. (Last author)DKFZ*

2022
Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41375-022-01587-0

Abstract: The 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.

Note: #LA:B062# / 2022 Jul;36(7):1759-1768

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. DKTK HD zentral (HD01)
3. DKTK BE zentral (BE01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2022

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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