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.DKFZ* ; Bourquin, J.-P. ; Korbel, J. O.DKFZ* ; 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 / 311 / #LA:A400#

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. DKTK HD zentral (HD01)
3. DKTK Koordinierungsstelle Berlin (BE01)
4. KKE Pädiatrische Leukämie (A400)
5. KKE Pädiatrische Onkologie (B310)
6. Mechanismen der genetischen Variation und Datenwissenschaft (B480)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

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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