Abstract

Mutations of the nucleophosmin (NPM1) gene, encoding for a nucleolar multifunctional protein, occur in approximately one-third of adult acute myeloid leukemia (AML). NPM1-mutated AML exhibits unique molecular, pathological, and clinical features, which led to its recognition as distinct entity in the 2017 World Health Organization (WHO) classification of myeloid neoplasms. Although WHO criteria for the diagnosis of NPM1-mutated AML are well established, its distinction from other AML entities may be difficult. Moreover, the percentage of blasts required to diagnose NPM1-mutated AML remains controversial. According to the European LeukemiaNet (ELN), determining the mutational status of NPM1 (together with FLT3) is mandatory for accurate relapse-risk assessment. NPM1 mutations are ideal targets for measurable residual disease (MRD) monitoring, since they are AML specific, frequent, very stable at relapse, and do not drive clonal hematopoiesis of undetermined significance. MRD monitoring by quantitative polymerase chain reaction of NPM1-mutant transcripts, possibly combined with ELN genetic-based risk stratification, can guide therapeutic decisions after remission. Furthermore, immunohistochemistry can be very useful in selected situations, such as diagnosis of NPM1-mutated myeloid sarcoma. Herein, we present 4 illustrative cases of NPM1-mutated AML that address important issues surrounding the biology, diagnosis, and therapy of this common form of leukemia.

REFERENCES

REFERENCES
1.
Grisendi
S
,
Mecucci
C
,
Falini
B
,
Pandolfi
PP
.
Nucleophosmin and cancer
.
Nat Rev Cancer
.
2006
;
6
(
7
):
493
-
505
.
2.
Falini
B
,
Mecucci
C
,
Tiacci
E
, et al;
GIMEMA Acute Leukemia Working Party
.
Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype
.
N Engl J Med
.
2005
;
352
(
3
):
254
-
266
.
3.
Falini
B
,
Brunetti
L
,
Sportoletti
P
,
Martelli
MP
.
NPM1-mutated acute myeloid leukemia: from bench to bedside
.
Blood
.
2020
;
136
(
15
):
1707
-
1721
.
4.
Falini
B
,
Bolli
N
,
Liso
A
, et al
.
Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications
.
Leukemia
.
2009
;
23
(
10
):
1731
-
1743
.
5.
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
.
6.
Cazzaniga
G
,
Dell’Oro
MG
,
Mecucci
C
, et al
.
Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype
.
Blood
.
2005
;
106
(
4
):
1419
-
1422
.
7.
Nagel
G
,
Weber
D
,
Fromm
E
, et al;
German-Austrian AML Study Group (AMLSG)
.
Epidemiological, genetic, and clinical characterization by age of newly diagnosed acute myeloid leukemia based on an academic population-based registry study (AMLSG BiO)
.
Ann Hematol
.
2017
;
96
(
12
):
1993
-
2003
.
8.
Arber
DA
,
Brunning
RD
,
Le Beau
MM
, et al
. Acute myeloid leukaemia with recurrent genetic abnormalities. In:
Swerdlow
S
, ed.
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues
,
Lyon
:
International Agency for Research on Cancer (IARC)
;
2017
:
129
-
149
.
9.
Falini
B
,
Martelli
MP
,
Pileri
SA
,
Mecucci
C
.
Molecular and alternative methods for diagnosis of acute myeloid leukemia with mutated NPM1: flexibility may help
.
Haematologica
.
2010
;
95
(
4
):
529
-
534
.
10.
Gorello
P
,
Cazzaniga
G
,
Alberti
F
, et al
.
Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations
.
Leukemia
.
2006
;
20
(
6
):
1103
-
1108
.
11.
Yang
F
,
Anekpuritanang
T
,
Press
RD
.
Clinical utility of next-generation sequencing in acute myeloid eukemia
.
Mol Diagn Ther
.
2020
;
24
(
1
):
1
-
13
.
12.
Falini
B
,
Martelli
MP
,
Bolli
N
, et al
.
Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia
.
Blood
.
2006
;
108
(
6
):
1999
-
2005
.
13.
Taylor
G
,
Ivey
A
,
Milner
B
,
Grimwade
D
,
Culligan
D
.
Acute myeloid leukaemia with mutated NPM1 presenting with extensive bone marrow necrosis and Charcot-Leyden crystals
.
Int J Hematol
.
2013
;
98
(
3
):
267
-
268
.
14.
Mendler
JH
,
Maharry
K
,
Becker
H
, et al
.
In rare acute myeloid leukemia patients harboring both RUNX1 and NPM1 mutations, RUNX1 mutations are unusual in structure and present in the germline
.
Haematologica
.
2013
;
98
(
8
):
e92
-
e94
.
15.
Döhner
H
,
Estey
E
,
Grimwade
D
, et al
.
Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel
.
Blood
.
2017
;
129
(
4
):
424
-
447
.
16.
Shlush
LI
,
Zandi
S
,
Mitchell
A
, et al;
HALT Pan-Leukemia Gene Panel Consortium
.
Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia [published correction appears in Nature. 2014;508:420]
.
Nature
.
2014
;
506
(
7488
):
328
-
333
.
17.
McKerrell
T
,
Park
N
,
Moreno
T
, et al;
Understanding Society Scientific Group
.
Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis
.
Cell Rep
.
2015
;
10
(
8
):
1239
-
1245
.
18.
Hasserjian
RP
,
Steensma
DP
,
Graubert
TA
,
Ebert
BL
.
Clonal hematopoiesis and measurable residual disease assessment in acute myeloid leukemia
.
Blood
.
2020
;
135
(
20
):
1729
-
1738
.
19.
Lachowiez
CA
,
Loghavi
S
,
Kadia
TM
, et al
.
Outcomes of older patients with NPM1-mutated AML: current treatments and the promise of venetoclax-based regimens
.
Blood Adv
.
2020
;
4
(
7
):
1311
-
1320
.
20.
Falini
B
,
Brunetti
L
,
Martelli
MP
.
Dactinomycin in NPM1-mutated acute myeloid leukemia
.
N Engl J Med
.
2015
;
373
(
12
):
1180
-
1182
.
21.
Martelli
MF
,
Di Ianni
M
,
Ruggeri
L
, et al
.
HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse
.
Blood
.
2014
;
124
(
4
):
638
-
644
.
22.
Schlenk
RF
,
Döhner
K
,
Krauter
J
, et al;
German-Austrian Acute Myeloid Leukemia Study Group
.
Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia
.
N Engl J Med
.
2008
;
358
(
18
):
1909
-
1918
.
23.
Bazarbachi
A
,
Labopin
M
,
Kharfan-Dabaja
MA
, et al
.
Allogeneic hematopoietic cell transplantation in acute myeloid leukemia with normal karyotype and isolated Nucleophosmin-1 (NPM1) mutation: outcome strongly correlates with disease status
.
Haematologica
.
2016
;
101
(
1
):
e34
-
e37
.
24.
Poiré
X
,
Labopin
M
,
Polge
E
, et al
.
Hematopoietic stem cell transplantation for adult patients with isolated NPM1 mutated acute myeloid leukemia in first remission
.
Am J Hematol
.
2019
;
94
(
2
):
231
-
239
.
25.
Döhner
K
,
Thiede
C
,
Jahn
N
, et al
.
Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia
.
Blood
.
2020
;
135
(
5
):
371
-
380
.
26.
Hills
RK
,
Castaigne
S
,
Appelbaum
FR
, et al
.
Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials
.
Lancet Oncol
.
2014
;
15
(
9
):
986
-
996
.
27.
Fournier
E
,
Duployez
N
,
Ducourneau
B
, et al
.
Mutational profile and benefit of gemtuzumab ozogamicin in acute myeloid leukemia
.
Blood
.
2020
;
135
(
8
):
542
-
546
.
28.
Schlenk
RF
,
Paschka
P
,
Krzykalla
J
, et al
.
Gemtuzumab ozogamicin in NPM1-mutated acute myeloid leukemia: early results from the prospective randomized AMLSG 09-09 phase III study
.
J Clin Oncol
.
2020
;
38
(
6
):
623
-
632
.
29.
Kapp-Schwoerer
S
,
Weber
D
,
Corbacioglu
A
, et al
.
Impact of gemtuzumab ozogamicin on MRD and relapse risk in NPM1 mutated AML patients: results from the AMLSG 09-09 Trial
.
Blood
.
2020;136(26):3041-3050
.
30.
Bazarbachi
A
,
Bug
G
,
Baron
F
, et al
.
Clinical practice recommendation on hematopoietic stem cell transplantation for acute myeloid leukemia patients with FLT3-internal tandem duplication: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
.
Haematologica
.
2020
;
105
(
6
):
1507
-
1516
.
31.
Röllig
C
,
Bornhäuser
M
,
Kramer
M
, et al
.
Allogeneic stem-cell transplantation in patients with NPM1-mutated acute myeloid leukemia: results from a prospective donor versus no-donor analysis of patients after upfront HLA typing within the SAL-AML 2003 trial [published correction appears in J Clin Oncol. 2015;33(13):1519]
.
J Clin Oncol
.
2015
;
33
(
5
):
403
-
410
.
32.
Straube
J
,
Ling
VY
,
Hill
GR
,
Lane
SW
.
The impact of age, NPM1mut, and FLT3ITD allelic ratio in patients with acute myeloid leukemia
.
Blood
.
2018
;
131
(
10
):
1148
-
1153
.
33.
Sakaguchi
M
,
Yamaguchi
H
,
Najima
Y
, et al
.
Prognostic impact of low allelic ratio FLT3-ITD and NPM1 mutation in acute myeloid leukemia
.
Blood Adv
.
2018
;
2
(
20
):
2744
-
2754
.
34.
Ivey
A
,
Hills
RK
,
Simpson
MA
, et al;
UK National Cancer Research Institute AML Working Group
.
Assessment of minimal residual disease in standard-risk AML
.
N Engl J Med
.
2016
;
374
(
5
):
422
-
433
.
35.
Krönke
J
,
Schlenk
RF
,
Jensen
KO
, et al
.
Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group
.
J Clin Oncol
.
2011
;
29
(
19
):
2709
-
2716
.
36.
Schnittger
S
,
Kern
W
,
Tschulik
C
, et al
.
Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML
.
Blood
.
2009
;
114
(
11
):
2220
-
2231
.
37.
Shayegi
N
,
Kramer
M
,
Bornhäuser
M
, et al;
Study Alliance Leukemia (SAL)
.
The level of residual disease based on mutant NPM1 is an independent prognostic factor for relapse and survival in AML
.
Blood
.
2013
;
122
(
1
):
83
-
92
.
38.
Balsat
M
,
Renneville
A
,
Thomas
X
, et al
.
Postinduction minimal residual disease predicts outcome and benefit from allogeneic stem cell transplantation in acute myeloid leukemia with NPM1 mutation: a study by the Acute Leukemia French Association Group
.
J Clin Oncol
.
2017
;
35
(
2
):
185
-
193
.
39.
Schwind
S
,
Jentzsch
M
,
Bach
E
,
Stasik
S
,
Thiede
C
,
Platzbecker
U
.
Use of minimal residual disease in acute myeloid leukemia therapy
.
Curr Treat Opt Oncol
.
2020
;
21
(1):
8
.
40.
Schuurhuis
GJ
,
Heuser
M
,
Freeman
S
, et al
.
Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party
.
Blood
.
2018
;
131
(
12
):
1275
-
1291
.
41.
Ommen
HB
,
Schnittger
S
,
Jovanovic
JV
, et al
.
Strikingly different molecular relapse kinetics in NPM1c, PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11 acute myeloid leukemias
.
Blood
.
2010
;
115
(
2
):
198
-
205
.
42.
Dillon
R
,
Potter
N
,
Freeman
S
,
Russel
N
.
How we use molecular minimal residual disease (MRD) testing in acute myeloid leukaemia (AML) [published online ahead of print 15 October 2020]
.
Br J Haematol
.
doi:10.1111/bjh.17185
.
43.
Greiner
J
,
Schneider
V
,
Schmitt
M
, et al
.
Immune responses against the mutated region of cytoplasmatic NPM1 might contribute to the favorable clinical outcome of AML patients with NPM1 mutations (NPM1mut)
.
Blood
.
2013
;
122
(
6
):
1087
-
1088
.
44.
Guolo
F
,
Minetto
P
,
Clavio
M
, et al
.
Longitudinal minimal residual disease (MRD) evaluation in acute myeloid leukaemia with NPM1 mutation: from definition of molecular relapse to MRD-driven salvage approach
.
Br J Haematol
.
2019
;
186
(
6
):
e223
-
e225
.
45.
Bataller
A
,
Oñate
G
,
Diaz-Beyá
M
, et al;
Grupo Cooperativo Para el Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias (CETLAM)
.
Acute myeloid leukemia with NPM1 mutation and favorable European LeukemiaNet category: outcome after preemptive intervention based on measurable residual disease
.
Br J Haematol
.
2020
;
191
(
1
):
52
-
61
.
46.
Kayser
S
,
Benner
A
,
Thiede
C
, et al
.
Pretransplant NPM1 MRD levels predict outcome after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia
.
Blood Cancer J
.
2016
;
6
(
7
):
e449
.
47.
Bill
M
,
Grimm
J
,
Jentzsch
M
, et al
.
Digital droplet PCR-based absolute quantification of pre-transplant NPM1 mutation burden predicts relapse in acute myeloid leukemia patients
.
Ann Hematol
.
2018
;
97
(
10
):
1757
-
1765
.
48.
Dillon
R
,
Hills
R
,
Freeman
S
, et al
.
Molecular MRD status and outcome after transplantation in NPM1-mutated AML
.
Blood
.
2020
;
135
(
9
):
680
-
688
.
49.
Platzbecker
U
,
Middeke
JM
,
Sockel
K
, et al
.
Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial
.
Lancet Oncol
.
2018
;
19
(
12
):
1668
-
1679
.
50.
Tiong
IS
,
Dillon
R
,
Ivey
A
, et al
.
Venetoclax induces rapid elimination of NPM1 mutant measurable residual disease in combination with low-intensity chemotherapy in acute myeloid leukaemia [published online ahead of print 26 May 2020]
.
Br J Haematol
.
doi: 10.1111/bjh.16722
.
51.
Lambert
J
,
Lambert
J
,
Nibourel
O
, et al
.
MRD assessed by WT1 and NPM1 transcript levels identifies distinct outcomes in AML patients and is influenced by gemtuzumab ozogamicin
.
Oncotarget
.
2014
;
5
(
15
):
6280
-
6288
.
52.
Luskin
MR
,
Huen
AO
,
Brooks
SA
, et al
.
NPM1 mutation is associated with leukemia cutis in acute myeloid leukemia with monocytic features
.
Haematologica
.
2015
;
100
(
10
):
e412
-
e414
.
53.
Ganzel
C
,
Manola
J
,
Douer
D
, et al
.
Extramedullary disease in adult acute myeloid leukemia is common but lacks independent significance: analysis of patients in ECOG-ACRIN Cancer Research Group trials, 1980-2008 [published correction appears in J Clin Oncol. 2017;35(2):263]
.
J Clin Oncol
.
2016
;
34
(
29
):
3544
-
3553
.
54.
Stone
RM
,
Mandrekar
SJ
,
Sanford
BL
, et al
.
Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation
.
N Engl J Med
.
2017
;
377
(
5
):
454
-
464
.
55.
Pratcorona
M
,
Brunet
S
,
Nomdedéu
J
, et al;
Grupo Cooperativo Para el Estudio y Tratamiento de las Leucemias Agudas Mieloblásticas
.
Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy
.
Blood
.
2013
;
121
(
14
):
2734
-
2738
.
56.
Hemmati
P
,
Terwey
TH
,
Vuong
LG
,
le Coutre
PD
,
Dorken
B
,
Arnold
R
.
Allogeneic stem cell transplantation for cytogenetically normal acute myeloid leukemia: impact of FLT3 and NPM1 mutational status
.
Blood
.
2013
;
122
(
21
):
2104
.
57.
Schlenk
RF
,
Kayser
S
,
Bullinger
L
, et al;
German-Austrian AML Study Group
.
Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation
.
Blood
.
2014
;
124
(
23
):
3441
-
3449
.
58.
Lussana
F
,
Caprioli
C
,
Stefanoni
P
, et al
.
Molecular detection of minimal residual disease before allogeneic stem cellt transplantation predicts a high incidence of early relapse in adult patients with NPM1 positive acute myeloid leukemia
.
Cancers (Basel)
.
2019
;
11
(
10
):
1455
.
59.
Fenwarth
L
,
Thomas
X
,
de Botton
S
, et al
.
A personalized approach to guide allogeneic stem cell transplantation in younger adults with acute myeloid leukemia [published online ahead of print 1 September 2020]
.
Blood
.
doi:10.1182/blood.2020005524
.
60.
Maakaron
JE
,
Mims
AS
.
Daunorubicin-cytarabine liposome (CPX-351) in the management of newly diagnosed secondary AML: a new twist on an old cocktail
.
Best Pract Res Clin Haematol
.
2019
;
32
(
2
):
127
-
133
.
61.
Falini
B
,
Macijewski
K
,
Weiss
T
, et al
.
Multilineage dysplasia has no impact on biologic, clinicopathologic, and prognostic features of AML with mutated nucleophosmin (NPM1)
.
Blood
.
2010
;
115
(
18
):
3776
-
3786
.
62.
Pasqualucci
L
,
Liso
A
,
Martelli
MP
, et al
.
Mutated nucleophosmin detects clonal multilineage involvement in acute myeloid leukemia: impact on WHO classification
.
Blood
.
2006
;
108
(
13
):
4146
-
4155
.
63.
Sportoletti
P
,
Varasano
E
,
Rossi
R
, et al
.
The human NPM1 mutation A perturbs megakaryopoiesis in a conditional mouse model
.
Blood
.
2013
;
121
(
17
):
3447
-
3458
.
64.
Prata
PH
,
Bally
C
,
Prebet
T
, et al
.
NPM1 mutation is not associated with prolonged complete remission in acute myeloid leukemia patients treated with hypomethylating agents
.
Haematologica
.
2018
;
103
(
10
):
e455
-
e457
.
65.
DiNardo
CD
,
Tiong
IS
,
Quaglieri
A
, et al
.
Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML
.
Blood
.
2020
;
135
(
11
):
791
-
803
.
66.
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
.
67.
Richard-Carpentier
G
,
DiNardo
CD
.
Venetoclax for the treatment of newly diagnosed acute myeloid leukemia in patients who are ineligible for intensive chemotherapy
.
Ther Adv Hematol
.
2019
;
10
:
2040620719882822
.
68.
Pollyea
DA
,
Amaya
M
,
Strati
P
,
Konopleva
MY
.
Venetoclax for AML: changing the treatment paradigm [published correction appears in Blood Adv. 2019;3(24):4326]
.
Blood Adv
.
2019
;
3
(
24
):
4326
-
4335
.
69.
NCRI
.
Recommendations for the management of patients with AML during the COVID19 outbreak: a statement from the NCRI AML Working Party.
https://www.rcpath.org/uploads/assets/d23030b6-7379-4f80-9ed9178c5f864343/Recommendations-for-the-management-of-patients-with-acute-myeloid-leukaemia-AML-during-the-COVID19-outbreak.pdf. Accessed 23 March 2020.
70.
Zeidan
AM
,
Boddu
PC
,
Patnaik
MM
, et al
.
Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts
.
Lancet Haematol
.
2020
;
7
(
8
):
e601
-
e612
.
71.
Farah
N
,
Burt
R
,
Ibrahim
AR
,
Baker
R
,
Kottaridis
PD
.
Concerns about how to use established minimal residual disease (MRD) monitoring in the treatment of NPM1-mutant AML following reduced intensity chemotherapy protocols for AML given as a result of the COVID-19 pandemic [published online ahead of print 1 July 2020]
.
Br J Haematol
.
doi: 10.1111/bjh.16985
.
72.
Becker
H
,
Marcucci
G
,
Maharry
K
, et al
.
Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: a Cancer and Leukemia Group B study
.
J Clin Oncol
.
2010
;
28
(
4
):
596
-
604
.
73.
Scholl
S
,
Theuer
C
,
Scheble
V
, et al
.
Clinical impact of nucleophosmin mutations and Flt3 internal tandem duplications in patients older than 60 yr with acute myeloid leukaemia
.
Eur J Haematol
.
2008
;
80
(
3
):
208
-
215
.
74.
Ostronoff
F
,
Othus
M
,
Lazenby
M
, et al
.
Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report [published correction appears in J Clin Oncol. 2015;33(15):1715]
.
J Clin Oncol
.
2015
;
33
(
10
):
1157
-
1164
.
75.
Schlenk
RF
,
Weber
D
,
Fiedler
W
, et al;
German-Austrian AML Study Group
.
Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD
.
Blood
.
2019
;
133
(
8
):
840
-
851
.
76.
Chua
CC
,
Roberts
AW
,
Reynolds
J
, et al
.
Chemotherapy and venetoclax in elderly acute myeloid leukemia trial (CAVEAT): a phase Ib dose-escalation study of venetoclax combined with modified intensive chemotherapy
.
J Clin Oncol
.
2020
;
38
(
30
):
3506
-
3517
.
77.
Aldoss
I
,
Nakamura
R
,
Yang
D
, et al
.
Favorable outcomes for allogeneic hematopoietic cell transplantation in elderly patients with NPM1-mutated and FLT3-ITD-negative acute myeloid leukemia
.
Bone Marrow Transplant
.
2020
;
55
(
2
):
473
-
475
.
78.
Jentzsch
M
,
Grimm
J
,
Bill
M
, et al
.
Outcomes of older patients with NPM1 mutated and FLT3-ITD negative acute myeloid leukemia receiving allogeneic transplantation
.
HemaSphere
.
2020
;
4
(
1
):
e326
.
79.
Krönke
J
,
Bullinger
L
,
Teleanu
V
, et al
.
Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia
.
Blood
.
2013
;
122
(
1
):
100
-
108
.
80.
Cocciardi
S
,
Dolnik
A
,
Kapp-Schwoerer
S
, et al
.
Clonal evolution patterns in acute myeloid leukemia with NPM1 mutation
.
Nat Commun
.
2019
;
10
(
1
):
2031
.
81.
Höllein
A
,
Meggendorfer
M
,
Dicker
F
, et al
.
NPM1 mutated AML can relapse with wild-type NPM1: persistent clonal hematopoiesis can drive relapse
.
Blood Adv
.
2018
;
2
(
22
):
3118
-
3125
.
82.
Herold
S
,
Sockel
K
,
Sayehli
C
, et al
.
Evolution of NPM1-negative therapy-related myelodysplastic syndromes following curative treatment of NPM1-mutant AML
.
Leukemia
.
2017
;
31
(
10
):
2247
-
2251
.
83.
Martín
I
,
Navarro
B
,
Villamón
E
, et al
.
Therapy-related acute myeloid leukemia developing 14 years after allogeneic hematopoietic stem cell transplantation, from a persistent R882H-DNMT3A mutated clone of patient origin
.
Exp Mol Pathol
.
2018
;
105
(
1
):
139
-
143
.
84.
Vallapureddy
R
,
Lasho
TL
,
Hoversten
K
, et al
.
Nucleophosmin 1 (NPM1) mutations in chronic myelomonocytic leukemia and their prognostic relevance
.
Am J Hematol
.
2017
;
92
(
10
):
E614
-
E618
.
85.
Patel
SS
,
Ho
C
,
Ptashkin
RN
, et al
.
Clinicopathologic and genetic characterization of nonacute NPM1-mutated myeloid neoplasms
.
Blood Adv
.
2019
;
3
(
9
):
1540
-
1545
.
86.
Martelli
MP
,
Pettirossi
V
,
Thiede
C
, et al
.
CD34+ cells from AML with mutated NPM1 harbor cytoplasmic mutated nucleophosmin and generate leukemia in immunocompromised mice
.
Blood
.
2010
;
116
(
19
):
3907
-
3922
.
87.
Montalban-Bravo
G
,
Kanagal-Shamanna
R
,
Sasaki
K
, et al
.
NPM1 mutations define a specific subgroup of MDS and MDS/MPN patients with favorable outcomes with intensive chemotherapy
.
Blood Adv
.
2019
;
3
(
6
):
922
-
933
.
88.
Forghieri
F
,
Paolini
A
,
Morselli
M
, et al
.
NPM1 mutations may reveal acute myeloid leukemia in cases otherwise morphologically diagnosed as myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms
.
Leuk Lymphoma
.
2015
;
56
(
11
):
3222
-
3226
.
89.
Papaemmanuil
E
,
Gerstung
M
,
Bullinger
L
, et al
.
Genomic classification and prognosis in acute myeloid leukemia
.
N Engl J Med
.
2016
;
374
(
23
):
2209
-
2221
.
90.
Boddu
P
,
Kantarjian
H
,
Borthakur
G
, et al
.
Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group
.
Blood Adv
.
2017
;
1
(
19
):
1546
-
1550
.
91.
Eisfeld
AK
,
Kohlschmidt
J
,
Mims
A
, et al
.
Additional gene mutations may refine the 2017 European LeukemiaNet classification in adult patients with de novo acute myeloid leukemia aged <60 years [published online ahead of print 27 May 2020]
.
Leukemia
.
doi: 10.1038/s41375-020-0872-3
.
92.
Jongen-Lavrencic
M
,
Grob
T
,
Hanekamp
D
, et al
.
Molecular minimal residual disease in acute myeloid leukemia
.
N Engl J Med
.
2018
;
378
(
13
):
1189
-
1199
.
93.
Ritterhouse
LL
,
Parilla
M
,
Zhen
CJ
, et al
.
Clinical validation and implementation of a measurable residual disease assay for NPM1 in acute myeloid leukemia by error-corrected next-generation sequencing
.
Mol Diagn Ther
.
2019
;
23
(
6
):
791
-
802
.
94.
Onecha
E
,
Linares
M
,
Rapado
I
, et al
.
A novel deep targeted sequencing method for minimal residual disease monitoring in acute myeloid leukemia
.
Haematologica
.
2019
;
104
(
2
):
288
-
296
.
95.
Thol
F
,
Gabdoulline
R
,
Liebich
A
, et al
.
Measurable residual disease monitoring by NGS before allogeneic hematopoietic cell transplantation in AML
.
Blood
.
2018
;
132
(
16
):
1703
-
1713
.
96.
Kasper
S
,
Breitenbuecher
F
,
Heidel
F
, et al
.
Targeting MCL-1 sensitizes FLT3-ITD-positive leukemias to cytotoxic therapies
.
Blood Cancer J
.
2012
;
2
(
3
):
e60
.
97.
Uckelmann
HJ
,
Kim
SM
,
Wong
EM
, et al
.
Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia
.
Science
.
2020
;
367
(
6477
):
586
-
590
.
98.
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
.
99.
Dzama
Margarita M
,
Steiner
Marlene
,
Rausch
Johanna
, et al
.
Synergistic targeting of FLT3 mutations in AML via combined menin-MLL and FLT3 inhibition
.
Blood
.
2020
;
136
(
21
):
2442
-
2456
.
100.
Fischer
MA
,
Friedlander
SY
,
Arrate
MP
, et al
.
Venetoclax response is enhanced by selective inhibitor of nuclear export compounds in hematologic malignancies
.
Blood Adv
.
2020
;
4
(
3
):
586
-
598
.
101.
Cela
I
,
Di Matteo
A
,
Federici
L
.
Nucleophosmin in its interaction with ligands
.
Int J Mol Sci
.
2020
;
21
(
14
):
E4885
.
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