Pediatric T-ALL type-1 and type-2 relapses develop along distinct pathways of clonal evolution

TY - JOUR

T1 - Pediatric T-ALL type-1 and type-2 relapses develop along distinct pathways of clonal evolution

AU - Richter-Pechańska, Paulina

AU - Kunz, Joachim B

AU - Rausch, Tobias

AU - Erarslan-Uysal, Büşra

AU - Bornhauser, Beat

AU - Frismantas, Viktoras

AU - Assenov, Yassen

AU - Zimmermann, Martin

AU - Happich, Margit

AU - von Knebel-Doeberitz, Caroline

AU - von Neuhoff, Nils

AU - Köhler, Rolf

AU - Stanulla, Martin

AU - Schrappe, Martin

AU - Cario, Gunnar

AU - Escherich, Gabriele

AU - Kirschner-Schwabe, Renate

AU - Eckert, Cornelia

AU - Avigad, Smadar

AU - Pfister, Stefan M

AU - Muckenthaler, Martina U

AU - Bourquin, Jean-Pierre

AU - Korbel, Jan O

AU - Kulozik, Andreas E

N1 - © 2022. The Author(s).

PY - 2022/7

Y1 - 2022/7

N2 - 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.

AB - 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.

KW - Child

KW - Clonal Evolution/genetics

KW - Humans

KW - Mutation

KW - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics

KW - Recurrence

U2 - 10.1038/s41375-022-01587-0

DO - 10.1038/s41375-022-01587-0

M3 - SCORING: Journal article

C2 - 35585141

VL - 36

SP - 1759

EP - 1768

JO - LEUKEMIA

JF - LEUKEMIA

SN - 0887-6924

IS - 7

ER -