Key Points

  • CH, including donor-engrafted CH, is highly prevalent among donors and recipients long-term after allo-HSCT.

  • CH clones variably expand at different levels of the hematopoietic hierarchy and can clonally evolve into subclones.

Abstract

Clonal hematopoiesis (CH) is associated with age and an increased risk of myeloid malignancies, cardiovascular risk, and all-cause mortality. We tested for CH in a setting where hematopoietic stem cells (HSCs) of the same individual are exposed to different degrees of proliferative stress and environments, ie, in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their respective related donors (n = 42 donor-recipient pairs). With a median follow-up time since allo-HSCT of 16 years (range, 10-32 years), we found a total of 35 mutations in 23 out of 84 (27.4%) study participants. Ten out of 42 donors (23.8%) and 13 out of 42 recipients (31%) had CH. CH was associated with older donor and recipient age. We identified 5 cases of donor-engrafted CH, with 1 case progressing into myelodysplastic syndrome in both donor and recipient. Four out of 5 cases showed increased clone size in recipients compared with donors. We further characterized the hematopoietic system in individuals with CH as follows: (1) CH was consistently present in myeloid cells but varied in penetrance in B and T cells; (2) colony-forming units (CFUs) revealed clonal evolution or multiple independent clones in individuals with multiple CH mutations; and (3) telomere shortening determined in granulocytes suggested ∼20 years of added proliferative history of HSCs in recipients compared with their donors, with telomere length in CH vs non-CH CFUs showing varying patterns. This study provides insight into the long-term behavior of the same human HSCs and respective CH development under different proliferative conditions.

REFERENCES

REFERENCES
1.
Jaiswal
S
,
Fontanillas
P
,
Flannick
J
, et al
.
Age-related clonal hematopoiesis associated with adverse outcomes
.
N Engl J Med
.
2014
;
371
(
26
):
2488
-
2498
.
2.
Genovese
G
,
Kähler
AK
,
Handsaker
RE
, et al
.
Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence
.
N Engl J Med
.
2014
;
371
(
26
):
2477
-
2487
.
3.
Xie
M
,
Lu
C
,
Wang
J
, et al
.
Age-related mutations associated with clonal hematopoietic expansion and malignancies
.
Nat Med
.
2014
;
20
(
12
):
1472
-
1478
.
4.
Zink
F
,
Stacey
SN
,
Norddahl
GL
, et al
.
Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly
.
Blood
.
2017
;
130
(
6
):
742
-
752
.
5.
Abelson
S
,
Collord
G
,
Ng
SWK
, et al
.
Prediction of acute myeloid leukaemia risk in healthy individuals
.
Nature
.
2018
;
559
(
7714
):
400
-
404
.
6.
Desai
P
,
Mencia-Trinchant
N
,
Savenkov
O
, et al
.
Somatic mutations precede acute myeloid leukemia years before diagnosis
.
Nat Med
.
2018
;
24
(
7
):
1015
-
1023
.
7.
Thol
F
,
Klesse
S
,
Köhler
L
, et al
.
Acute myeloid leukemia derived from lympho-myeloid clonal hematopoiesis
.
Leukemia
.
2017
;
31
(
6
):
1286
-
1295
.
8.
Gibson
CJ
,
Lindsley
RC
,
Tchekmedyian
V
, et al
.
Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma
.
J Clin Oncol
.
2017
;
35
(
14
):
1598
-
1605
.
9.
Coombs
CC
,
Zehir
A
,
Devlin
SM
, et al
.
Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes
.
Cell Stem Cell
.
2017
;
21
(
3
):
374
-
382.e4
.
10.
Fuster
JJ
,
MacLauchlan
S
,
Zuriaga
MA
, et al
.
Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice
.
Science
.
2017
;
355
(
6327
):
842
-
847
.
11.
Jaiswal
S
,
Natarajan
P
,
Silver
AJ
, et al
.
Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease
.
N Engl J Med
.
2017
;
377
(
2
):
111
-
121
.
12.
Wolach
O
,
Sellar
RS
,
Martinod
K
, et al
.
Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms
.
Sci Transl Med
.
2018
;
10
(
436
):
eaan8292
.
13.
Wynn
RF
,
Cross
MA
,
Hatton
C
, et al
.
Accelerated telomere shortening in young recipients of allogeneic bone-marrow transplants
.
Lancet
.
1998
;
351
(
9097
):
178
-
181
.
14.
Mathioudakis
G
,
Storb
R
,
McSweeney
PA
, et al
.
Polyclonal hematopoiesis with variable telomere shortening in human long-term allogeneic marrow graft recipients
.
Blood
.
2000
;
96
(
12
):
3991
-
3994
.
15.
Rufer
N
,
Brümmendorf
TH
,
Chapuis
B
,
Helg
C
,
Lansdorp
PM
,
Roosnek
E
.
Accelerated telomere shortening in hematological lineages is limited to the first year following stem cell transplantation
.
Blood
.
2001
;
97
(
2
):
575
-
577
.
16.
Takizawa
H
,
Boettcher
S
,
Manz
MG
.
Demand-adapted regulation of early hematopoiesis in infection and inflammation
.
Blood
.
2012
;
119
(
13
):
2991
-
3002
.
17.
Chitre
S
,
Stölzel
F
,
Cuthill
K
, et al
.
Clonal hematopoiesis in patients with multiple myeloma undergoing autologous stem cell transplantation
.
Leukemia
.
2018
;
32
(
9
):
2020
-
2024
.
18.
Fialkow
PJ
,
Thomas
ED
,
Bryant
JI
,
Neiman
PE
.
Leukaemic transformation of engrafted human marrow cells in vivo
.
Lancet
.
1971
;
1
(
7693
):
251
-
255
.
19.
Hertenstein
B
,
Hambach
L
,
Bacigalupo
A
, et al;
Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation
.
Development of leukemia in donor cells after allogeneic stem cell transplantation—a survey of the European Group for Blood and Marrow Transplantation (EBMT)
.
Haematologica
.
2005
;
90
(
7
):
969
-
975
.
20.
Kato
M
,
Yamashita
T
,
Suzuki
R
, et al
.
Donor cell-derived hematological malignancy: a survey by the Japan Society for Hematopoietic Cell Transplantation
.
Leukemia
.
2016
;
30
(
8
):
1742
-
1745
.
21.
Frick
M
,
Chan
W
,
Arends
CM
, et al
.
Role of donor clonal hematopoiesis in allogeneic hematopoietic stem-cell transplantation
.
J Clin Oncol
.
2019
;
37
(
5
):
375
-
385
.
22.
Fritsch
K
,
Pigeot
S
,
Feng
X
, et al
.
Engineered humanized bone organs maintain human hematopoiesis in vivo [published correction appears in Exp Hematol. 2019;72:72]
.
Exp Hematol
.
2018
;
61
:
45
-
51.e5
.
23.
Cawthon
RM
.
Telomere measurement by quantitative PCR
.
Nucleic Acids Res
.
2002
;
30
(
10
):
e47
.
24.
Cawthon
RM
.
Telomere length measurement by a novel monochrome multiplex quantitative PCR method
.
Nucleic Acids Res
.
2009
;
37
(
3
):
e21
.
25.
Wenn
K
,
Tomala
L
,
Wilop
S
, et al
.
Telomere length at diagnosis of chronic phase chronic myeloid leukemia (CML-CP) identifies a subgroup with favourable prognostic parameters and molecular response according to the ELN criteria after 12 months of treatment with nilotinib
.
Leukemia
.
2015
;
29
(
12
):
2402
-
2404
.
26.
Ventura Ferreira
MS
,
Crysandt
M
,
Ziegler
P
, et al
.
Evidence for a pre-existing telomere deficit in non-clonal hematopoietic stem cells in patients with acute myeloid leukemia
.
Ann Hematol
.
2017
;
96
(
9
):
1457
-
1461
.
27.
Sturm
M
,
Schroeder
C
,
Bauer
P
.
SeqPurge: highly-sensitive adapter trimming for paired-end NGS data
.
BMC Bioinformatics
.
2016
;
17
(
1
):
208
.
28.
Li
H
,
Durbin
R
.
Fast and accurate short read alignment with Burrows-Wheeler transform
.
Bioinformatics
.
2009
;
25
(
14
):
1754
-
1760
.
29.
McKenna
A
,
Hanna
M
,
Banks
E
, et al
.
The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data
.
Genome Res
.
2010
;
20
(
9
):
1297
-
1303
.
30.
Smith
T
,
Heger
A
,
Sudbery
I
.
UMI-tools: modeling sequencing errors in Unique Molecular Identifiers to improve quantification accuracy
.
Genome Res
.
2017
;
27
(
3
):
491
-
499
.
31.
Li
H
,
Handsaker
B
,
Wysoker
A
, et al;
1000 Genome Project Data Processing Subgroup
.
The Sequence Alignment/Map format and SAMtools
.
Bioinformatics
.
2009
;
25
(
16
):
2078
-
2079
.
32.
Koboldt
DC
,
Zhang
Q
,
Larson
DE
, et al
.
VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing
.
Genome Res
.
2012
;
22
(
3
):
568
-
576
.
33.
Sherry
ST
,
Ward
MH
,
Kholodov
M
, et al
.
dbSNP: the NCBI database of genetic variation
.
Nucleic Acids Res
.
2001
;
29
(
1
):
308
-
311
.
34.
Forbes
SA
,
Beare
D
,
Boutselakis
H
, et al
.
COSMIC: somatic cancer genetics at high-resolution
.
Nucleic Acids Res
.
2017
;
45
(
D1
):
D777
-
D783
.
35.
Cingolani
P
,
Patel
VM
,
Coon
M
, et al
.
Using Drosophila melanogaster as a model for genotoxic chemical mutational studies with a new program, SnpSift
.
Front Genet
.
2012
;
3
:
35
.
36.
Cingolani
P
,
Platts
A
,
Wang
L
, et al
.
A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3
.
Fly (Austin)
.
2012
;
6
(
2
):
80
-
92
.
37.
Thorvaldsdóttir
H
,
Robinson
JT
,
Mesirov
JP
.
Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration
.
Brief Bioinform
.
2013
;
14
(
2
):
178
-
192
.
38.
Buscarlet
M
,
Provost
S
,
Zada
YF
, et al
.
DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions
.
Blood
.
2017
;
130
(
6
):
753
-
762
.
39.
Welch
JS
,
Ley
TJ
,
Link
DC
, et al
.
The origin and evolution of mutations in acute myeloid leukemia
.
Cell
.
2012
;
150
(
2
):
264
-
278
.
40.
Alexandrov
LB
,
Nik-Zainal
S
,
Wedge
DC
, et al;
ICGC PedBrain
.
Signatures of mutational processes in human cancer [published correction appears in Nature. 2013;502(7470):258]
.
Nature
.
2013
;
500
(
7463
):
415
-
421
.
41.
Young
AL
,
Challen
GA
,
Birmann
BM
,
Druley
TE
.
Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults
.
Nat Commun
.
2016
;
7
(
1
):
12484
.
42.
Buscarlet
M
,
Provost
S
,
Zada
YF
, et al
.
Lineage restriction analyses in CHIP indicate myeloid bias for TET2 and multipotent stem cell origin for DNMT3A
.
Blood
.
2018
;
132
(
3
):
277
-
280
.
43.
Arends
CM
,
Galan-Sousa
J
,
Hoyer
K
, et al
.
Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis
.
Leukemia
.
2018
;
32
(
9
):
1908
-
1919
.
44.
Blackburn
EH
,
Epel
ES
,
Lin
J
.
Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection
.
Science
.
2015
;
350
(
6265
):
1193
-
1198
.
45.
Brümmendorf
TH
,
Balabanov
S
.
Telomere length dynamics in normal hematopoiesis and in disease states characterized by increased stem cell turnover
.
Leukemia
.
2006
;
20
(
10
):
1706
-
1716
.
46.
Jeong
M
,
Park
HJ
,
Celik
H
, et al
.
Loss of Dnmt3a immortalizes hematopoietic stem cells in vivo
.
Cell Rep
.
2018
;
23
(
1
):
1
-
10
.
47.
Allsopp
RC
,
Morin
GB
,
DePinho
R
,
Harley
CB
,
Weissman
IL
.
Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation
.
Blood
.
2003
;
102
(
2
):
517
-
520
.
48.
Gonzalo
S
,
Jaco
I
,
Fraga
MF
, et al
.
DNA methyltransferases control telomere length and telomere recombination in mammalian cells
.
Nat Cell Biol
.
2006
;
8
(
4
):
416
-
424
.
49.
Fabre
MA
,
McKerrell
T
,
Zwiebel
M
, et al
.
Concordance for clonal hematopoiesis is limited in elderly twins
.
Blood
.
2020
;
135
(
4
):
269
-
273
.
50.
Hansen
JW
,
Pedersen
DA
,
Larsen
LA
, et al
.
​Clonal hematopoiesis in elderly twins: concordance, discordance, and mortality
.
Blood
.
2020
;
135
(
4
):
261
-
268
.
You do not currently have access to this content.

Sign in via your Institution

Sign In