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Sci Transl Med DOI:10.1126/scitranslmed.abb7661

Distinct evolutionary paths in chronic lymphocytic leukemia during resistance to the graft-versus-leukemia effect.

Publication TypeJournal Article
Year of Publication2020
AuthorsBachireddy, P, Ennis, C, Nguyen, VN, Gohil, SH, Clement, K, Shukla, SA, Forman, J, Barkas, N, Freeman, S, Bavli, N, Elagina, L, Leshchiner, I, Mohammad, AW, Mathewson, ND, Keskin, DB, Rassenti, LZ, Kipps, TJ, Brown, JR, Getz, G, Ho, VT, Gnirke, A, Neuberg, D, Soiffer, RJ, Ritz, J, Alyea, EP, Kharchenko, PV, Wu, CJ
JournalSci Transl Med
Date Published2020 Sep 16

Leukemic relapse remains a major barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive hematologic malignancies. The basis for relapse of advanced lymphoid malignancies remains incompletely understood and may involve escape from the graft-versus-leukemia (GvL) effect. We hypothesized that for patients with chronic lymphocytic leukemia (CLL) treated with allo-HSCT, leukemic cell-intrinsic features influence transplant outcomes by directing the evolutionary trajectories of CLL cells. Integrated genetic, transcriptomic, and epigenetic analyses of CLL cells from 10 patients revealed that the clinical kinetics of post-HSCT relapse are shaped by distinct molecular dynamics. Early relapses after allo-HSCT exhibited notable genetic stability; single CLL cell transcriptional analysis demonstrated a cellular heterogeneity that was static over time. In contrast, CLL cells relapsing late after allo-HSCT displayed notable genetic evolution and evidence of neoantigen depletion, consistent with marked single-cell transcriptional shifts that were unique to each patient. We observed a greater rate of epigenetic change for late relapses not seen in early relapses or relapses after chemotherapy alone, suggesting that the selection pressures of the GvL bottleneck are unlike those imposed by chemotherapy. No selective advantage for human leukocyte antigen (HLA) loss was observed, even when present in pretransplant subpopulations. Gain of stem cell modules was a common signature associated with leukemia relapse regardless of posttransplant relapse kinetics. These data elucidate the biological pathways that underlie GvL resistance and posttransplant relapse.


PubMed ID32938797