PMID- 32938797
OWN - NLM
STAT- MEDLINE
DCOM- 20210623
LR  - 20220716
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Print)
IS  - 1946-6234 (Linking)
VI  - 12
IP  - 561
DP  - 2020 Sep 16
TI  - Distinct evolutionary paths in chronic lymphocytic leukemia during resistance to 
      the graft-versus-leukemia effect.
LID - 10.1126/scitranslmed.abb7661 [doi]
LID - eabb7661
AB  - 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.
CI  - Copyright (c) 2020 The Authors, some rights reserved; exclusive licensee American 
      Association for the Advancement of Science. No claim to original U.S. Government 
      Works.
FAU - Bachireddy, Pavan
AU  - Bachireddy P
AUID- ORCID: 0000-0002-8698-4957
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02215, USA.
AD  - Harvard Medical School, Boston, MA 02115, USA.
AD  - Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
FAU - Ennis, Christina
AU  - Ennis C
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02215, USA.
FAU - Nguyen, Vinhkhang N
AU  - Nguyen VN
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02215, USA.
FAU - Gohil, Satyen H
AU  - Gohil SH
AUID- ORCID: 0000-0003-0484-991X
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02215, USA.
AD  - Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
AD  - Department of Academic Haematology, University College London, London WC1E 6BT, 
      UK.
FAU - Clement, Kendell
AU  - Clement K
AUID- ORCID: 0000-0003-3808-0811
AD  - Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
AD  - Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, 
      USA.
FAU - Shukla, Sachet A
AU  - Shukla SA
AUID- ORCID: 0000-0003-2445-3584
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02215, USA.
AD  - Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
FAU - Forman, Juliet
AU  - Forman J
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02215, USA.
AD  - Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
FAU - Barkas, Nikolaos
AU  - Barkas N
AUID- ORCID: 0000-0002-4675-0718
AD  - Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
FAU - Freeman, Samuel
AU  - Freeman S
AUID- ORCID: 0000-0001-8285-0057
AD  - Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
FAU - Bavli, Natalie
AU  - Bavli N
AD  - Division of Hematology and Oncology, UT Southwestern, Dallas, TX 75390, USA.
FAU - Elagina, Liudmila
AU  - Elagina L
AD  - Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
FAU - Leshchiner, Ignaty
AU  - Leshchiner I
AD  - Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
FAU - Mohammad, Arman W
AU  - Mohammad AW
AD  - Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
FAU - Mathewson, Nathan D
AU  - Mathewson ND
AUID- ORCID: 0000-0002-8895-2609
AD  - Harvard Medical School, Boston, MA 02115, USA.
AD  - Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
AD  - Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 
      Boston, MA 02215, USA.
FAU - Keskin, Derin B
AU  - Keskin DB
AUID- ORCID: 0000-0002-8496-6181
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02215, USA.
AD  - Harvard Medical School, Boston, MA 02115, USA.
AD  - Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
FAU - Rassenti, Laura Z
AU  - Rassenti LZ
AD  - Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, 
      USA.
FAU - Kipps, Thomas J
AU  - Kipps TJ
AUID- ORCID: 0000-0002-0064-4549
AD  - Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, 
      USA.
FAU - Brown, Jennifer R
AU  - Brown JR
AUID- ORCID: 0000-0003-2040-4961
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02215, USA.
AD  - Harvard Medical School, Boston, MA 02115, USA.
AD  - Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
FAU - Getz, Gad
AU  - Getz G
AUID- ORCID: 0000-0002-0936-0753
AD  - Harvard Medical School, Boston, MA 02115, USA.
AD  - Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
AD  - Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, 
      USA.
AD  - Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
FAU - Ho, Vincent T
AU  - Ho VT
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02215, USA.
AD  - Harvard Medical School, Boston, MA 02115, USA.
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
FAU - Gnirke, Andreas
AU  - Gnirke A
AD  - Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
FAU - Neuberg, Donna
AU  - Neuberg D
AUID- ORCID: 0000-0003-2566-3145
AD  - Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
FAU - Soiffer, Robert J
AU  - Soiffer RJ
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02215, USA.
AD  - Harvard Medical School, Boston, MA 02115, USA.
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
FAU - Ritz, Jerome
AU  - Ritz J
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02215, USA.
AD  - Harvard Medical School, Boston, MA 02115, USA.
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
FAU - Alyea, Edwin P
AU  - Alyea EP
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02215, USA.
AD  - Harvard Medical School, Boston, MA 02115, USA.
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
FAU - Kharchenko, Peter V
AU  - Kharchenko PV
AUID- ORCID: 0000-0002-6036-5875
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, 
      USA.
AD  - Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
FAU - Wu, Catherine J
AU  - Wu CJ
AUID- ORCID: 0000-0002-3348-5054
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, MA 02215, USA. cwu@partners.org.
AD  - Harvard Medical School, Boston, MA 02115, USA.
AD  - Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
LA  - eng
GR  - U10 CA180861/CA/NCI NIH HHS/United States
GR  - P01 CA229092/CA/NCI NIH HHS/United States
GR  - P50 CA101942/CA/NCI NIH HHS/United States
GR  - R01 HL131768/HL/NHLBI NIH HHS/United States
GR  - T32 HG002295/HG/NHGRI NIH HHS/United States
GR  - R50 CA211482/CA/NCI NIH HHS/United States
GR  - P01 CA206978/CA/NCI NIH HHS/United States
GR  - R01 CA155010/CA/NCI NIH HHS/United States
GR  - UG1 CA233338/CA/NCI NIH HHS/United States
GR  - P30 CA006516/CA/NCI NIH HHS/United States
GR  - R21 CA216772/CA/NCI NIH HHS/United States
GR  - L30 CA231679/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (HLA Antigens)
SB  - IM
MH  - *Graft vs Host Disease
MH  - Graft vs Leukemia Effect
MH  - HLA Antigens
MH  - *Hematopoietic Stem Cell Transplantation
MH  - Humans
MH  - *Leukemia, Lymphocytic, Chronic, B-Cell/genetics/therapy
MH  - Transplantation, Homologous
PMC - PMC7829680
MID - NIHMS1657310
EDAT- 2020/09/18 06:00
MHDA- 2021/06/24 06:00
PMCR- 2021/03/16
CRDT- 2020/09/17 05:38
PHST- 2020/03/21 00:00 [received]
PHST- 2020/07/24 00:00 [accepted]
PHST- 2020/09/17 05:38 [entrez]
PHST- 2020/09/18 06:00 [pubmed]
PHST- 2021/06/24 06:00 [medline]
PHST- 2021/03/16 00:00 [pmc-release]
AID - 12/561/eabb7661 [pii]
AID - 10.1126/scitranslmed.abb7661 [doi]
PST - ppublish
SO  - Sci Transl Med. 2020 Sep 16;12(561):eabb7661. doi: 10.1126/scitranslmed.abb7661.