Pediatric T-ALL type-1 and type-2 relapses develop along distinct pathways of clonal evolution
Paulina Richter‐Pechańska, Joachim B. Kunz, Tobias Rausch, Büşra Erarslan-Uysal, Beat Bornhäuser, Viktoras Frismantas, Yassen Assenov, Martin Zimmermann, Margit Happich, Caroline von Knebel-Doeberitz, Nils von Neuhoff, Rolf Köhler, Martin Stanulla, Martin Schrappe, Gunnar Cario, Gabriele Escherich, Renate Kirschner‐Schwabe, Cornelia Eckert, Smadar Avigad, Stefan M. Pfister, Martina U. Muckenthaler, Jean‐Pierre Bourquin, Jan O. Korbel, Andreas E. Kulozik
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.