PMID- 24550281
OWN - NLM
STAT- MEDLINE
DCOM- 20140415
LR  - 20220408
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 111
IP  - 7
DP  - 2014 Feb 18
TI  - Preleukemic mutations in human acute myeloid leukemia affect epigenetic 
      regulators and persist in remission.
PG  - 2548-53
LID - 10.1073/pnas.1324297111 [doi]
AB  - Cancer is widely characterized by the sequential acquisition of genetic lesions 
      in a single lineage of cells. Our previous studies have shown that, in acute 
      myeloid leukemia (AML), mutation acquisition occurs in functionally normal 
      hematopoietic stem cells (HSCs). These preleukemic HSCs harbor some, but not all, 
      of the mutations found in the leukemic cells. We report here the identification 
      of patterns of mutation acquisition in human AML. Our findings support a model in 
      which mutations in "landscaping" genes, involved in global chromatin changes such 
      as DNA methylation, histone modification, and chromatin looping, occur early in 
      the evolution of AML, whereas mutations in "proliferative" genes occur late. 
      Additionally, we analyze the persistence of preleukemic mutations in patients in 
      remission and find CD34+ progenitor cells and various mature cells that harbor 
      preleukemic mutations. These findings indicate that preleukemic HSCs can survive 
      induction chemotherapy, identifying these cells as a reservoir for the 
      reevolution of relapsed disease. Finally, through the study of several cases of 
      relapsed AML, we demonstrate various evolutionary patterns for the generation of 
      relapsed disease and show that some of these patterns are consistent with 
      involvement of preleukemic HSCs. These findings provide key insights into the 
      monitoring of minimal residual disease and the identification of therapeutic 
      targets in human AML.
FAU - Corces-Zimmerman, M Ryan
AU  - Corces-Zimmerman MR
AD  - Program in Cancer Biology, Ludwig Center, Cancer Institute, Institute for Stem 
      Cell Biology and Regenerative Medicine, and Department of Medicine, Division of 
      Hematology, Stanford University School of Medicine, Stanford, CA 94305.
FAU - Hong, Wan-Jen
AU  - Hong WJ
FAU - Weissman, Irving L
AU  - Weissman IL
FAU - Medeiros, Bruno C
AU  - Medeiros BC
FAU - Majeti, Ravindra
AU  - Majeti R
LA  - eng
GR  - R01 CA188055/CA/NCI NIH HHS/United States
GR  - U01 HL099999/HL/NHLBI NIH HHS/United States
GR  - R01 CA086017/CA/NCI NIH HHS/United States
GR  - T32CA009287-35/CA/NCI NIH HHS/United States
GR  - T32 CA009287/CA/NCI NIH HHS/United States
GR  - U01HL099999/HL/NHLBI NIH HHS/United States
GR  - R01 CA086065/CA/NCI NIH HHS/United States
GR  - U01 HL099995/HL/NHLBI NIH HHS/United States
GR  - F31 CA180659/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20140203
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antigens, CD34)
SB  - IM
CIN - Cell Stem Cell. 2014 Apr 3;14(4):421-2. PMID: 24702991
MH  - Antigens, CD34/metabolism
MH  - Base Sequence
MH  - Clonal Evolution/*genetics
MH  - Epigenesis, Genetic/*genetics
MH  - Exome/genetics
MH  - Flow Cytometry
MH  - Genotype
MH  - Hematopoietic Stem Cells/*chemistry
MH  - Humans
MH  - Leukemia, Myeloid, Acute/*genetics
MH  - *Models, Biological
MH  - Molecular Sequence Data
MH  - Mutation/genetics
MH  - Preleukemia/*genetics
MH  - Sequence Analysis, DNA
PMC - PMC3932921
OTO - NOTNLM
OT  - clonal evolution
OT  - preleukemia
COIS- The authors declare no conflict of interest.
EDAT- 2014/02/20 06:00
MHDA- 2014/04/16 06:00
PMCR- 2014/08/18
CRDT- 2014/02/20 06:00
PHST- 2014/02/20 06:00 [entrez]
PHST- 2014/02/20 06:00 [pubmed]
PHST- 2014/04/16 06:00 [medline]
PHST- 2014/08/18 00:00 [pmc-release]
AID - 1324297111 [pii]
AID - 201324297 [pii]
AID - 10.1073/pnas.1324297111 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2548-53. doi: 
      10.1073/pnas.1324297111. Epub 2014 Feb 3.