Abstract

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the (oligo)clonal expansion of myeloid progenitor cells. Despite advances in treatment, AML remains challenging to cure, particularly in patients with specific genetic abnormalities. Menin inhibitors have emerged as a promising therapeutic approach, targeting key genetic drivers of AML, such as KMT2A (lysine methyl transferase 2A) rearrangements and NPM1 mutations. Here, we review the clinical value of menin inhibitors, highlighting their mechanism of action, efficacy, safety, and potential to transform AML treatment.

1.
Hanahan
D
.
Hallmarks of cancer: new dimensions
.
Cancer Discov
.
2022
;
12
(
1
):
31
-
46
.
2.
Hanahan
D
,
Weinberg
RA
.
Hallmarks of cancer: the next generation
.
Cell
.
2011
;
144
(
5
):
646
-
674
.
3.
Cancer Genome Atlas Research Network
,
Ley
TJ
,
Miller
C
, et al
.
Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia
.
N Engl J Med
.
2013
;
368
(
22
):
2059
-
2074
.
4.
Jones
PA
,
Baylin
SB
.
The epigenomics of cancer
.
Cell
.
2007
;
128
(
4
):
683
-
692
.
5.
Silverman
LR
,
Holland
JF
,
Weinberg
RS
, et al
.
Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes
.
Leukemia
.
1993
;
7
(
suppl 1
):
21
-
29
.
6.
Jüttermann
R
,
Li
E
,
Jaenisch
R
.
Toxicity of 5-aza-2’-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation
.
Proc Natl Acad Sci U S A
.
1994
;
91
(
25
):
11797
-
11801
.
7.
Fenaux
P
,
Mufti
GJ
,
Hellstrom-Lindberg
E
, et al
.
Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study
.
Lancet Oncol
.
2009
;
10
(
3
):
223
-
232
.
8.
Dombret
H
,
Seymour
JF
,
Butrym
A
, et al
.
International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts
.
Blood
.
2015
;
126
(
3
):
291
-
299
.
9.
Kantarjian
H
,
Oki
Y
,
Garcia-Manero
G
, et al
.
Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia
.
Blood
.
2007
;
109
(
1
):
52
-
57
.
10.
DiNardo
CD
,
Jonas
BA
,
Pullarkat
V
, et al
.
Azacitidine and venetoclax in previously untreated acute myeloid leukemia
.
N Engl J Med
.
2020
;
383
(
7
):
617
-
629
.
11.
Montesinos
P
,
Recher
C
,
Vives
S
, et al
.
Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia
.
N Engl J Med
.
2022
;
386
(
16
):
1519
-
1531
.
12.
Lübbert
M
,
Wijermans
PW
,
Kicinski
M
, et al
.
10-Day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial
.
Lancet Haematol
.
2023
;
10
(
11
):
e879
-
e889
.
13.
Marks
PA
,
Rifkind
RA
,
Richon
VM
,
Breslow
R
,
Miller
T
,
Kelly
WK
.
Histone deacetylases and cancer: causes and therapies
.
Nat Rev Cancer
.
2001
;
1
(
3
):
194
-
202
.
14.
Dawson
MA
,
Kouzarides
T
,
Huntly
BJP
.
Targeting epigenetic readers in cancer
.
N Engl J Med
.
2012
;
367
(
7
):
647
-
657
.
15.
Perner
F
,
Armstrong
SA
.
Targeting chromatin complexes in myeloid malignancies and beyond: from basic mechanisms to clinical innovation
.
Cells
.
2020
;
9
(
12
):
2721
.
16.
Garcia-Manero
G
,
Podoltsev
NA
,
Othus
M
, et al
.
A randomized phase III study of standard versus high-dose cytarabine with or without vorinostat for AML
.
Leukemia
.
2024
;
38
(
1
):
58
-
66
.
17.
Yokoyama
A
,
Cleary
ML
.
Menin critically links MLL proteins with LEDGF on cancer-associated target genes
.
Cancer Cell
.
2008
;
14
(
1
):
36
-
46
.
18.
El Ashkar
S
,
Schwaller
J
,
Pieters
T
, et al
.
LEDGF/p75 is dispensable for hematopoiesis but essential for MLL-rearranged leukemogenesis
.
Blood
.
2018
;
131
(
1
):
95
-
107
.
19.
Feng
Z
,
Ma
J
,
Hua
X
.
Epigenetic regulation by the menin pathway
.
Endocr Relat Cancer
.
2017
;
24
(
10
):
T147
-
T159
.
20.
Brunetti
L
,
Gundry
MC
,
Sorcini
D
, et al
.
Mutant NPM1 maintains the leukemic state through HOX expression
.
Cancer Cell
.
2018
;
34
(
3
):
499
-
512.e9
.
21.
Woolthuis
CM
,
Han
L
,
Verkaik-Schakel
RN
, et al
.
Downregulation of MEIS1 impairs long-term expansion of CD34+ NPM1-mutated acute myeloid leukemia cells
.
Leukemia
.
2012
;
26
(
4
):
848
-
853
.
22.
Falini
B
,
Mecucci
C
,
Tiacci
E
, et al
.
Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype
.
N Engl J Med
.
2005
;
352
(
3
):
254
-
266
.
23.
Uckelmann
HJ
,
Haarer
EL
,
Takeda
R
, et al
.
Mutant NPM1 directly regulates oncogenic transcription in acute myeloid leukemia
.
Cancer Discov
.
2023
;
13
(
3
):
746
-
765
.
24.
Wang
XQD
,
Fan
D
,
Han
Q
, et al
.
Mutant NPM1 hijacks transcriptional hubs to maintain pathogenic gene programs in acute myeloid leukemia
.
Cancer Discov
.
2023
;
13
(
3
):
724
-
745
.
25.
Issa
GC
,
Zarka
J
,
Sasaki
K
, et al
.
Predictors of outcomes in adults with acute myeloid leukemia and KMT2A rearrangements
.
Blood Cancer J
.
2021
;
11
(
9
):
162
.
26.
Döhner
H
,
Wei
AH
,
Appelbaum
FR
, et al
.
Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN
.
Blood
.
2022
;
140
(
12
):
1345
-
1377
.
27.
Yokoyama
A
,
Somervaille
TCP
,
Smith
KS
,
Rozenblatt-Rosen
O
,
Meyerson
M
,
Cleary
ML
.
The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis
.
Cell
.
2005
;
123
(
2
):
207
-
218
.
28.
Grembecka
J
,
He
S
,
Shi
A
, et al
.
Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia
.
Nat Chem Biol
.
2012
;
8
(
3
):
277
-
284
.
29.
Borkin
D
,
He
S
,
Miao
H
, et al
.
Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo
.
Cancer Cell
.
2015
;
27
(
4
):
589
-
602
.
30.
Kuhn
MW
,
Song
E
,
Feng
Z
, et al
.
Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia
.
Cancer Discov
.
2016
;
6
(
10
):
1166
-
1181
.
31.
Klossowski
S
,
Miao
H
,
Kempinska
K
, et al
.
Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia
.
J Clin Invest
.
2020
;
130
(
2
):
981
-
997
.
32.
Krivtsov
A V
,
Evans
K
,
Gadrey
JY
, et al
.
A menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia
.
Cancer Cell
.
2019
;
36
(
6
):
660
-
673.e11
.
33.
Uckelmann
HJ
,
Kim
SM
,
Wong
EM
, et al
.
Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia
.
Science (1979)
.
2020
;
367
(
6477
):
586
-
590
.
34.
Issa
GC
,
Aldoss
I
,
DiPersio
J
, et al
.
The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia
.
Nature
.
2023
;
615
(
7954
):
920
-
924
.
35.
Issa
GC
,
Aldoss
I
,
Thirman
MJ
, et al
.
Menin inhibition with revumenib for KMT2A-rearranged relapsed or refractory acute leukemia (AUGMENT-101)
.
J Clin Oncol
.
2025
;
43
(
1
):
75
-
84
.
36.
Zeidner
J
,
Lin
T
,
Welkie
R
, et al
.
Phase 1B study of azacitidine, venetoclax and revumenib in newly diagnosed older adults with NPM1 mutated or KMT2A rearranged AML: interim results of dose escalation from the BEATAML consortium [abstract]
.
Hemasphere
.
2024
:
S134
.
37.
Issa
GC
,
Cuglievan
B
,
DiNardo
CD
, et al
.
Early results of the phase I/II study investigating the all-oral combination of the menin inhibitor revumenib (SNDX-5613) with decitabine/cedazuridine (ASTX727) and venetoclax in acute myeloid leukemia (SAVE) [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
58
.
38.
Fathi
A
,
Wang
E
,
Issa
G
, et al
.
P504: updated data for ziftomenib in patients with NPM1-mutated relapsed or refractory acute myeloid leukemia
.
Hemasphere
.
2023
;
7
(
S3
):
e19161da
.
39.
Jabbour
E
,
Searle
E
,
Abdul-Hay
M
, et al
.
A first-in-human phase 1 study of the menin-KMT2A (MLL1) inhibitor JNJ-75276617 in adult patients with relapsed/refractory acute leukemia harboring KMT2A or NPM1 alterations [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
57
.
40.
Daver
N
,
Erba
H
,
Watts
JM
, et al
.
First-in-human phase 1/2 study of the menin-MLL inhibitor DSP-5336 in patients with relapsed or refractory acute leukemia: updated results from dose escalation [abstract]
.
Hemasphere
.
2024
:
S132
.
41.
Lancet
J
,
Ravandi
F
,
Montesinos
P
, et al
.
Covalent menin inhibitor Bmf-219 in patients with relapsed or refractory (R/R) acute leukemia (AL): preliminary phase 1 data from the Covalent-101 study [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
2916
.
42.
Rausch
J
,
Dzama
MM
,
Dolgikh
N
, et al
.
Menin inhibitor ziftomenib (KO-539) synergizes with drugs targeting chromatin regulation or apoptosis and sensitizes acute myeloid leukemia with MLL rearrangement or NPM1 mutation to venetoclax
.
Haematologica
.
2023
;
108
(
10
):
2837
-
2843
.
43.
Kwon
MC
,
Thuring
JW
,
Querolle
O
, et al
.
Preclinical efficacy of the potent, selective menin-KMT2A inhibitor JNJ-75276617 (bleximenib) in KMT2A- and NPM1-altered leukemias
.
Blood
.
2024
;
144
(
11
):
1206
-
1220
.
44.
Wei
A
,
Searle
E
,
Aldos
I
, et al
.
Phase 1B study of the menin-KMT2A inhibitor JNJ-75276617 in combination with venetoclax and azacitidine in relapsed/refractory acute myeloid leukemia with alterations in KMT2A or NPM1 [abstract]
.
Hemasphere
.
2024
:
S133
.
45.
Perner
F
,
Stein
EM
,
Wenge
DV
, et al
.
MEN1 mutations mediate clinical resistance to menin inhibition
.
Nature
.
2023
;
615
(
7954
):
913
-
919
.
46.
Soto-Feliciano
YM
,
Sánchez-Rivera
FJ
,
Perner
F
, et al
.
A molecular switch between mammalian MLL complexes dictates response to menin-MLL inhibition
.
Cancer Discov
.
2023
;
13
(
1
):
146
-
169
.
47.
Zhou
X
,
Zhang
L
,
Aryal
S
, et al
.
Epigenetic regulation of non-canonical menin targets modulates menin inhibitor response in acute myeloid leukemia
.
Blood
.
2024
;
144
(
19
):
2018
-
2032
.
48.
Hogeling
S
,
DM
,
La Rose
N
, et al
.
Bleximenib, the novel menin-KMT2A inhibitor JNJ-75276617 impairs long-term proliferation and immune evasion in acute myeloid leukemia
.
Haematologica
.
Published online 19 December 2024
https://doi.org/10.3324/haematol.2024.285616.
49.
Sparbier
CE
,
Gillespie
A
,
Gomez
J
, et al
.
Targeting menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes
.
Nat Cell Biol
.
2023
;
25
(
2
):
258
-
272
.
50.
Heikamp
EB
,
Henrich
JA
,
Perner
F
, et al
.
The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML
.
Blood
.
2022
;
139
(
6
):
894
-
906
.
51.
Barajas
JM
,
Rasouli
M
,
Umeda
M
, et al
.
Acute myeloid leukemias with UBTF tandem duplications are sensitive to menin inhibitors
.
Blood
.
2024
;
143
(
7
):
619
-
630
.
52.
Schmidt
L
,
Heyes
E
,
Scheiblecker
L
, et al
.
CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex
.
Leukemia
.
2019
;
33
(
7
):
1608
-
1619
.
You do not currently have access to this content.
Sign in via your Institution