https://orcid.org/0000-0002-5322-1961
Key Points
In AML with 3q26 rearrangements, the MECOM/CTBP complex represses CEBPA transcription by binding to the +42-kilobase enhancer.
CEBPA transcription is increased, and myeloid differentiation induced in AML with 3q26 rearrangements upon MECOM degradation.
Abstract
The transcription factor MECOM, located at 3q26, is essential for hematopoietic stem cells in healthy individuals. Enhancer translocations, due to 3q26 rearrangements, drive out-of-context MECOM expression in one of the most aggressive subtypes of acute myeloid leukemia (AML). Aberrantly expressed MECOM is essential for the survival and immature phenotype of these leukemia cells. Direct depletion of MECOM using an endogenous auxin-inducible degron immediately upregulates expression of CEBPA, which encodes a transcription factor required for neutrophil development and is frequently mutated in other AML subtypes. MECOM depletion is accompanied by a severe loss of CD34 and gain of mature myeloid cell surface marker CD15. MECOM exerts its inhibitory effect on differentiation by binding to the +42-kilobase CEBPA enhancer. This is partially dependent on the interaction between MECOM and its corepressor CTBP2. We demonstrate that CEBPA overexpression can bypass the MECOM-mediated block of differentiation. In addition, patients with AML with MECOM overexpression through enhancer hijacking show significantly reduced CEBPA levels. Our study directly connects 2 major players in normal and malignant hematopoiesis, MECOM and CEBPA, and unveils how MECOM maintains self-renewal by repressing CEBPA-induced differentiation.
References
1.
Yuasa
H
, Oike
Y
, Iwama
A
, et al. Oncogenic transcription factor Evi1 regulates hematopoietic stem cell proliferation through GATA-2 expression
. EMBO J
. 2005
;24
(11
):1976
-1987
.2.
Nielsen
M
, Vermont
CL
, Aten
E
, et al. Deletion of the 3q26 region including the EVI1 and MDS1 genes in a neonate with congenital thrombocytopenia and subsequent aplastic anaemia
. J Med Genet
. 2012
;49
(9
):598
-600
.3.
Ottema
S
, Mulet-Lazaro
R
, Beverloo
HB
, et al. Atypical 3q26/MECOM rearrangements genocopy inv(3)/t(3;3) in acute myeloid leukemia
. Blood
. 2020
;136
(2
):224
-234
.4.
Lugthart
S
, van Drunen
E
, van Norden
Y
, et al. High EVI1 levels predict adverse outcome in acute myeloid leukemia: prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated
. Blood
. 2008
;111
(8
):4329
-4337
.5.
Barjesteh van Waalwijk van Doorn-Khosrovani
S
, Erpelinck
C
, van Putten
WL
, et al. High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients
. Blood
. 2003
;101
(3
):837
-845
.6.
Gröschel
S
, Lugthart
S
, Schlenk
RF
, et al. High EVI1 expression predicts outcome in younger adult patients with acute myeloid leukemia and is associated with distinct cytogenetic abnormalities
. J Clin Oncol
. 2010
;28
(12
):2101
-2107
.7.
Lugthart
S
, Gröschel
S
, Beverloo
HB
, et al. Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia
. J Clin Oncol
. 2010
;28
(24
):3890
-3898
.8.
Morishita
K
, Parganas
E
, William
CL
, et al. Activation of EVI1 gene expression in human acute myelogenous leukemias by translocations spanning 300-400 kilobases on chromosome band 3q26
. Proc Natl Acad Sci U S A
. 1992
;89
(9
):3937
-3941
.9.
Gröschel
S
, Sanders
MA
, Hoogenboezem
R
, et al. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia
. Cell
. 2014
;157
(2
):369
-381
.10.
Yamazaki
H
, Suzuki
M
, Otsuki
A
, et al. A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression
. Cancer Cell
. 2014
;25
(4
):415
-427
.11.
Smeenk
L
, Ottema
S
, Mulet-Lazaro
R
, et al. Selective requirement of MYB for oncogenic hyperactivation of a translocated enhancer in leukemia
. Cancer Discov
. 2021
;11
(11
):2868
-2883
.12.
Pastoors
D
, Havermans
M
, Mulet-Lazaro
R
, et al. Oncogene EVI1 drives acute myeloid leukemia via a targetable interaction with CTBP2
. Sci Adv
. 2024
;10
(20
):eadk9076
.13.
Gómez-Benito
M
, Conchillo
A
, García
MA
, et al. EVI1 controls proliferation in acute myeloid leukaemia through modulation of miR-1-2
. Br J Cancer
. 2010
;103
(8
):1292
-1296
.14.
Ayoub
E
, Wilson
MP
, McGrath
KE
, et al. EVI1 overexpression reprograms hematopoiesis via upregulation of Spi1 transcription
. Nat Commun
. 2018
;9
(1
):4239
.15.
Mizuno
H
, Koya
J
, Masamoto
Y
, Kagoya
Y
, Kurokawa
M
. Evi1 upregulates Fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation
. Cancer Sci
. 2021
;112
(10
):4112
-4126
.16.
Schmoellerl
J
, Barbosa
IAM
, Minnich
M
, et al. EVI1 drives leukemogenesis through aberrant ERG activation
. Blood
. 2023
;141
(5
):453
-466
.17.
Grasedieck
S
, Cabantog
A
, MacPhee
L
, et al. The retinoic acid receptor co-factor NRIP1 is uniquely upregulated and represents a therapeutic target in acute myeloid leukemia with chromosome 3q rearrangements
. Haematologica
. 2022
;107
(8
):1758
-1772
.18.
Vinothkumar
K
, Chanda
S
, Singh
VK
, et al. EVI1 upregulates PTGS1 (COX1) and decreases the action of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia cells
. Int J Hematol
. 2023
;117
(1
):110
-120
.19.
De Weer
A
, Van der Meulen
J
, Rondou
P
, et al. EVI1-mediated down regulation of MIR449A is essential for the survival of EVI1 positive leukaemic cells
. Br J Haematol
. 2011
;154
(3
):337
-348
.20.
Glass
C
, Wuertzer
C
, Cui
X
, et al. Global identification of EVI1 target genes in acute myeloid leukemia
. PLoS One
. 2013
;8
(6
):e67134
.21.
Dickstein
J
, Senyuk
V
, Premanand
K
, et al. Methylation and silencing of miRNA-124 by EVI1 and self-renewal exhaustion of hematopoietic stem cells in murine myelodysplastic syndrome
. Proc Natl Acad Sci U S A
. 2010
;107
(21
):9783
-9788
.22.
Senyuk
V
, Sinha
KK
, Li
D
, Rinaldi
CR
, Yanamandra
S
, Nucifora
G
. Repression of RUNX1 activity by EVI1: a new role of EVI1 in leukemogenesis
. Cancer Res
. 2007
;67
(12
):5658
-5666
.23.
Yoshimi
A
, Goyama
S
, Watanabe-Okochi
N
, et al. Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins
. Blood
. 2011
;117
(13
):3617
-3628
.24.
Wilson
M
, Tsakraklides
V
, Tran
M
, Xiao
YY
, Zhang
Y
, Perkins
AS
. EVI1 interferes with myeloid maturation via transcriptional repression of Cebpa, via binding to two far downstream regulatory elements
. J Biol Chem
. 2016
;291
(26
):13591
-13607
.25.
Avellino
R
, Havermans
M
, Erpelinck
C
, et al. An autonomous CEBPA enhancer specific for myeloid-lineage priming and neutrophilic differentiation
. Blood
. 2016
;127
(24
):2991
-3003
.26.
Guo
H
, Cooper
S
, Friedman
AD
. In vivo deletion of the Cebpa +37 kb enhancer markedly reduces Cebpa mRNA in myeloid progenitors but not in non-hematopoietic tissues to impair granulopoiesis
. PLoS One
. 2016
;11
(3
):e0150809
.27.
Nishimura
K
, Fukagawa
T
, Takisawa
H
, Kakimoto
T
, Kanemaki
M
. An auxin-based degron system for the rapid depletion of proteins in nonplant cells
. Nat Methods
. 2009
;6
(12
):917
-922
.28.
Tavor
S
, Park
DJ
, Gery
S
, Vuong
PT
, Gombart
AF
, Koeffler
HP
. Restoration of C/EBPalpha expression in a BCR-ABL+ cell line induces terminal granulocytic differentiation
. J Biol Chem
. 2003
;278
(52
):52651
-52659
.29.
Herzog
VA
, Reichholf
B
, Neumann
T
, et al. Thiol-linked alkylation of RNA to assess expression dynamics
. Nat Methods
. 2017
;14
(12
):1198
-1204
.30.
Avellino
R
, Mulet-Lazaro
R
, Havermans
M
, et al. Induced cell-autonomous neutropenia systemically perturbs hematopoiesis in Cebpa enhancer-null mice
. Blood Adv
. 2022
;6
(5
):1406
-1419
.31.
Cooper
S
, Guo
H
, Friedman
AD
. The +37 kb Cebpa enhancer is critical for Cebpa myeloid gene expression and contains functional sites that bind SCL, GATA2, C/EBPalpha, PU.1, and additional Ets factors
. PLoS One
. 2015
;10
(5
):e0126385
.32.
Loke
J
, Assi
SA
, Imperato
MR
, et al. RUNX1-ETO and RUNX1-EVI1 differentially reprogram the chromatin landscape in t(8;21) and t(3;21) AML
. Cell Rep
. 2017
;19
(8
):1654
-1668
.33.
Loke
J
, Chin
PS
, Keane
P
, et al. C/EBPα overrides epigenetic reprogramming by oncogenic transcription factors in acute myeloid leukemia
. Blood Adv
. 2018
;2
(3
):271
-284
.34.
Zhen
T
, Cao
Y
, Ren
G
, et al. RUNX1 and CBFβ-SMMHC transactivate target genes together in abnormal myeloid progenitors for leukemia development
. Blood
. 2020
;136
(21
):2373
-2385
.35.
Fleming
TJ
, Antoszewski
M
, Lambo
S
, et al. CEBPA repression by MECOM blocks differentiation to drive aggressive leukemias
. Blood
. 2025
;146
(25
):3019
-3035
.© 2025 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
2025
You do not currently have access to this content.
This feature is available to Subscribers Only
Sign In or Create an Account Close Modal