Key Points

  • Hippo kinase STK4 is downregulated in del(20q) MDS and MPN patients, and inactivation in mice recapitulates clinical disease features.

  • Heterozygous Hippo kinase loss cooperates with JAK2-V617F to promote myelofibrosis through IRAK1-mediated innate immune activation.

Abstract

Heterozygous deletions within chromosome 20q, or del(20q), are frequent cytogenetic abnormalities detected in hematologic malignancies. To date, identification of genes in the del(20q) common deleted region that contribute to disease development have remained elusive. Through assessment of patient gene expression, we have identified STK4 (encoding Hippo kinase MST1) as a 20q gene that is downregulated below haploinsufficient amounts in myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). Hematopoietic-specific gene inactivation in mice revealed Hippo kinase loss to induce splenomegaly, thrombocytopenia, megakaryocytic dysplasia, and a propensity for chronic granulocytosis; phenotypes that closely resemble those observed in patients harboring del(20q). In a JAK2-V617F model, heterozygous Hippo kinase inactivation led to accelerated development of lethal myelofibrosis, recapitulating adverse MPN disease progression and revealing a novel genetic interaction between these 2 molecular events. Quantitative serum protein profiling showed that myelofibrotic transformation in mice was associated with cooperative effects of JAK2-V617F and Hippo kinase inactivation on innate immune-associated proinflammatory cytokine production, including IL-1β and IL-6. Mechanistically, MST1 interacted with IRAK1, and shRNA-mediated knockdown was sufficient to increase IRAK1-dependent innate immune activation of NF-κB in human myeloid cells. Consistent with this, treatment with a small molecule IRAK1/4 inhibitor rescued the aberrantly elevated IL-1β production in the JAK2-V617F MPN model. This study identified Hippo kinase MST1 (STK4) as having a central role in the biology of del(20q)-associated hematologic malignancies and revealed a novel molecular basis of adverse MPN progression that may be therapeutically exploitable via IRAK1 inhibition.

REFERENCES

REFERENCES
1.
Fröhling
S
,
Döhner
H
.
Chromosomal abnormalities in cancer
.
N Engl J Med
.
2008
;
359
(
7
):
722
-
734
.
2.
Ebert
BL
,
Pretz
J
,
Bosco
J
, et al
.
Identification of RPS14 as a 5q- syndrome gene by RNA interference screen
.
Nature
.
2008
;
451
(
7176
):
335
-
339
.
3.
Starczynowski
DT
,
Kuchenbauer
F
,
Argiropoulos
B
, et al
.
Identification of miR-145 and miR-146a as mediators of the 5q-syndrome phenotype
.
Nat Med
.
2010
;
16
(
1
):
49
-
58
.
4.
McNerney
ME
,
Brown
CD
,
Wang
X
, et al
.
CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia
.
Blood
.
2013
;
121
(
6
):
975
-
983
.
5.
List
A
,
Ebert
BL
,
Fenaux
P
.
A decade of progress in myelodysplastic syndrome with chromosome 5q deletion
.
Leukemia
.
2018
;
32
(
7
):
1493
-
1499
.
6.
Rhyasen
GW
,
Bolanos
L
,
Fang
J
, et al
.
Targeting IRAK1 as a therapeutic approach for myelodysplastic syndrome
.
Cancer Cell
.
2013
;
24
(
1
):
90
-
104
.
7.
Schneider
RK
,
Ademà
V
,
Heckl
D
, et al
.
Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS
.
Cancer Cell
.
2014
;
26
(
4
):
509
-
520
.
8.
Asimakopoulos
FA
,
Green
AR
.
Deletions of chromosome 20q and the pathogenesis of myeloproliferative disorders
.
Br J Haematol
.
1996
;
95
(
2
):
219
-
226
.
9.
Kralovics
R
,
Skoda
RC
.
Molecular pathogenesis of Philadelphia chromosome negative myeloproliferative disorders
.
Blood Rev
.
2005
;
19
(
1
):
1
-
13
.
10.
Bacher
U
,
Schnittger
S
,
Kern
W
,
Weiss
T
,
Haferlach
T
,
Haferlach
C
.
Distribution of cytogenetic abnormalities in myelodysplastic syndromes, Philadelphia negative myeloproliferative neoplasms, and the overlap MDS/MPN category
.
Ann Hematol
.
2009
;
88
(
12
):
1207
-
1213
.
11.
Bejar
R
,
Levine
R
,
Ebert
BL
.
Unraveling the molecular pathophysiology of myelodysplastic syndromes
.
J Clin Oncol
.
2011
;
29
(
5
):
504
-
515
.
12.
Patnaik
MM
,
Tefferi
A
.
Cytogenetic and molecular abnormalities in chronic myelomonocytic leukemia
.
Blood Cancer J
.
2016
;
6
:
e393
.
13.
Hussein
K
,
Van Dyke
DL
,
Tefferi
A
.
Conventional cytogenetics in myelofibrosis: literature review and discussion
.
Eur J Haematol
.
2009
;
82
(
5
):
329
-
338
.
14.
Bench
AJ
,
Nacheva
EP
,
Hood
TL
, et al;
UK Cancer Cytogenetics Group (UKCCG)
.
Chromosome 20 deletions in myeloid malignancies: reduction of the common deleted region, generation of a PAC/BAC contig and identification of candidate genes
.
Oncogene
.
2000
;
19
(
34
):
3902
-
3913
.
15.
Douet-Guilbert
N
,
Basinko
A
,
Morel
F
, et al
.
Chromosome 20 deletions in myelodysplastic syndromes and Philadelphia-chromosome-negative myeloproliferative disorders: characterization by molecular cytogenetics of commonly deleted and retained regions
.
Ann Hematol
.
2008
;
87
(
7
):
537
-
544
.
16.
Bacher
U
,
Haferlach
T
,
Schnittger
S
, et al
.
Investigation of 305 patients with myelodysplastic syndromes and 20q deletion for associated cytogenetic and molecular genetic lesions and their prognostic impact
.
Br J Haematol
.
2014
;
164
(
6
):
822
-
833
.
17.
Aziz
A
,
Baxter
EJ
,
Edwards
C
, et al
.
Cooperativity of imprinted genes inactivated by acquired chromosome 20q deletions
.
J Clin Invest
.
2013
;
123
(
5
):
2169
-
2182
.
18.
Perna
F
,
Gurvich
N
,
Hoya-Arias
R
, et al
.
Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells: possible role in 20q- polycythemia vera
.
Blood
.
2010
;
116
(
15
):
2812
-
2821
.
19.
Heinrichs
S
,
Conover
LF
,
Bueso-Ramos
CE
, et al
.
MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy
.
eLife
.
2013
;
2
(
2
):
e00825
.
20.
Clarke
M
,
Dumon
S
,
Ward
C
, et al
.
MYBL2 haploinsufficiency increases susceptibility to age-related haematopoietic neoplasia
.
Leukemia
.
2013
;
27
(
3
):
661
-
670
.
21.
Jobe
F
,
Patel
B
,
Kuzmanovic
T
, et al
.
Deletion of Ptpn1 induces myeloproliferative neoplasm
.
Leukemia
.
2017
;
31
(
5
):
1229
-
1234
.
22.
Yu
FX
,
Zhao
B
,
Guan
KL
.
Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer
.
Cell
.
2015
;
163
(
4
):
811
-
828
.
23.
Cottini
F
,
Hideshima
T
,
Xu
C
, et al
.
Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers
.
Nat Med
.
2014
;
20
(
6
):
599
-
606
.
24.
Jansson
L
,
Larsson
J
.
Normal hematopoietic stem cell function in mice with enforced expression of the Hippo signaling effector YAP1
.
PLoS One
.
2012
;
7
(
2
):
e32013
.
25.
Kurz
ARM
,
Catz
SD
,
Sperandio
M
.
Noncanonical Hippo Signalling in the Regulation of Leukocyte Function
.
Trends Immunol
.
2018
;
39
(
8
):
656
-
669
.
26.
Katagiri
K
,
Imamura
M
,
Kinashi
T
.
Spatiotemporal regulation of the kinase Mst1 by binding protein RAPL is critical for lymphocyte polarity and adhesion
.
Nat Immunol
.
2006
;
7
(
9
):
919
-
928
.
27.
Zhou
D
,
Medoff
BD
,
Chen
L
, et al
.
The Nore1B/Mst1 complex restrains antigen receptor-induced proliferation of naïve T cells
.
Proc Natl Acad Sci USA
.
2008
;
105
(
51
):
20321
-
20326
.
28.
Ueda
Y
,
Katagiri
K
,
Tomiyama
T
, et al
.
Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus
.
Nat Commun
.
2012
;
3
:
1098
.
29.
Mou
F
,
Praskova
M
,
Xia
F
, et al
.
The Mst1 and Mst2 kinases control activation of rho family GTPases and thymic egress of mature thymocytes
.
J Exp Med
.
2012
;
209
(
4
):
741
-
759
.
30.
Kurz
AR
,
Pruenster
M
,
Rohwedder
I
, et al
.
MST1-dependent vesicle trafficking regulates neutrophil transmigration through the vascular basement membrane
.
J Clin Invest
.
2016
;
126
(
11
):
4125
-
4139
.
31.
Geng
J
,
Sun
X
,
Wang
P
, et al
.
Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity
.
Nat Immunol
.
2015
;
16
(
11
):
1142
-
1152
.
32.
Li
C
,
Bi
Y
,
Li
Y
, et al
.
Dendritic cell MST1 inhibits Th17 differentiation
.
Nat Commun
.
2017
;
8
:
14275
.
33.
Du
X
,
Wen
J
,
Wang
Y
, et al
.
Hippo/Mst signalling couples metabolic state and immune function of CD8α+ dendritic cells
.
Nature
.
2018
;
558
(
7708
):
141
-
145
.
34.
Nehme
NT
,
Schmid
JP
,
Debeurme
F
, et al
.
MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival
.
Blood
.
2012
;
119
(
15
):
3458
-
3468
.
35.
Abdollahpour
H
,
Appaswamy
G
,
Kotlarz
D
, et al
.
The phenotype of human STK4 deficiency
.
Blood
.
2012
;
119
(
15
):
3450
-
3457
.
36.
Halacli
SO
,
Ayvaz
DC
,
Sun-Tan
C
, et al
.
STK4 (MST1) deficiency in two siblings with autoimmune cytopenias: A novel mutation
.
Clin Immunol
.
2015
;
161
(
2
):
316
-
323
.
37.
Gerstung
M
,
Pellagatti
A
,
Malcovati
L
, et al
.
Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes
.
Nat Commun
.
2015
;
6
:
5901
.
38.
Skov
V
,
Larsen
TS
,
Thomassen
M
, et al
.
Whole-blood transcriptional profiling of interferon-inducible genes identifies highly upregulated IFI27 in primary myelofibrosis
.
Eur J Haematol
.
2011
;
87
(
1
):
54
-
60
.
39.
Rampal
R
,
Al-Shahrour
F
,
Abdel-Wahab
O
, et al
.
Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis
.
Blood
.
2014
;
123
(
22
):
e123
-
e133
.
40.
Meng
Z
,
Moroishi
T
,
Mottier-Pavie
V
, et al
.
MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway
.
Nat Commun
.
2015
;
6
:
8357
.
41.
Plouffe
SW
,
Meng
Z
,
Lin
KC
, et al
.
Characterization of Hippo Pathway Components by Gene Inactivation
.
Mol Cell
.
2016
;
64
(
5
):
993
-
1008
.
42.
Gupta
R
,
Soupir
CP
,
Johari
V
,
Hasserjian
RP
.
Myelodysplastic syndrome with isolated deletion of chromosome 20q: an indolent disease with minimal morphological dysplasia and frequent thrombocytopenic presentation
.
Br J Haematol
.
2007
;
139
(
2
):
265
-
268
.
43.
Braun
T
,
de Botton
S
,
Taksin
AL
, et al
.
Characteristics and outcome of myelodysplastic syndromes (MDS) with isolated 20q deletion: a report on 62 cases
.
Leuk Res
.
2011
;
35
(
7
):
863
-
867
.
44.
Machiela
MJ
,
Zhou
W
,
Caporaso
N
, et al
.
Mosaic chromosome 20q deletions are more frequent in the aging population
.
Blood Adv
.
2017
;
1
(
6
):
380
-
385
.
45.
Loh
PR
,
Genovese
G
,
Handsaker
RE
, et al
.
Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations
.
Nature
.
2018
;
559
(
7714
):
350
-
355
.
46.
Song
J
,
Hussaini
M
,
Zhang
H
, et al
.
Comparison of the Mutational Profiles of Primary Myelofibrosis, Polycythemia Vera, and Essential Thrombocytosis
.
Am J Clin Pathol
.
2017
;
147
(
5
):
444
-
452
.
47.
Wassie
E
,
Finke
C
,
Gangat
N
, et al
.
A compendium of cytogenetic abnormalities in myelofibrosis: molecular and phenotypic correlates in 826 patients
.
Br J Haematol
.
2015
;
169
(
1
):
71
-
76
.
48.
Li
J
,
Kent
DG
,
Chen
E
,
Green
AR
.
Mouse models of myeloproliferative neoplasms: JAK of all grades
.
Dis Model Mech
.
2011
;
4
(
3
):
311
-
317
.
49.
Mondet
J
,
Hussein
K
,
Mossuz
P
.
Circulating Cytokine Levels as Markers of Inflammation in Philadelphia Negative Myeloproliferative Neoplasms: Diagnostic and Prognostic Interest
.
Mediators Inflamm
.
2015
;
2015
:
670580
.
50.
Kleppe
M
,
Kwak
M
,
Koppikar
P
, et al
.
JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response
.
Cancer Discov
.
2015
;
5
(
3
):
316
-
331
.
51.
Kleppe
M
,
Koche
R
,
Zou
L
, et al
.
Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms [published corrections appears in Cancer Cell. 2018;33(4):785-787]
.
Cancer Cell
.
2018
;
33
(
1
):
29
-
43.e7
.
52.
Mao
Y
,
Yen
H
,
Sun
Y
,
Lv
Z
,
Huang
R
.
Development of non-overlapping multiplex antibody arrays for the quantitative measurement of 400 human and 200 mouse proteins in parallel
.
J Immunol
.
2014
;
192
(
suppl 1
):
69.17
.
53.
Li
W
,
Xiao
J
,
Zhou
X
, et al
.
STK4 regulates TLR pathways and protects against chronic inflammation-related hepatocellular carcinoma
.
J Clin Invest
.
2015
;
125
(
11
):
4239
-
4254
.
54.
Tefferi
A
,
Vaidya
R
,
Caramazza
D
,
Finke
C
,
Lasho
T
,
Pardanani
A
.
Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study
.
J Clin Oncol
.
2011
;
29
(
10
):
1356
-
1363
.
55.
Fang
J
,
Bolanos
LC
,
Choi
K
, et al
.
Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia [published correction appears in Nat Immunol. 2017;18;474]
.
Nat Immunol
.
2017
;
18
(
2
):
236
-
245
.
56.
Varney
ME
,
Niederkorn
M
,
Konno
H
, et al
.
Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling
.
J Exp Med
.
2015
;
212
(
11
):
1967
-
1985
.
57.
Chen
ZJ
.
Ubiquitin signalling in the NF-kappaB pathway
.
Nat Cell Biol
.
2005
;
7
(
8
):
758
-
765
.
58.
Hosseini
MM
,
Kurtz
SE
,
Abdelhamed
S
, et al
.
Inhibition of interleukin-1 receptor-associated kinase-1 is a therapeutic strategy for acute myeloid leukemia subtypes
.
Leukemia
.
2018
;
32
(
11
):
2374
-
2387
.
59.
Barreyro
L
,
Chlon
TM
,
Starczynowski
DT
.
Chronic immune response dysregulation in MDS pathogenesis
.
Blood
.
2018
;
132
(
15
):
1553
-
1560
.
60.
Sallman
DA
,
List
A
.
The central role of inflammatory signaling in the pathogenesis of myelodysplastic syndromes
.
Blood
.
2019
;
133
(
10
):
1039
-
1048
.
61.
Kristinsson
SY
,
Björkholm
M
,
Hultcrantz
M
,
Derolf
AR
,
Landgren
O
,
Goldin
LR
.
Chronic immune stimulation might act as a trigger for the development of acute myeloid leukemia or myelodysplastic syndromes
.
J Clin Oncol
.
2011
;
29
(
21
):
2897
-
2903
.
62.
Chen
X
,
Eksioglu
EA
,
Zhou
J
, et al
.
Induction of myelodysplasia by myeloid-derived suppressor cells
.
J Clin Invest
.
2013
;
123
(
11
):
4595
-
4611
.
63.
Lee
SC
,
North
K
,
Kim
E
, et al
.
Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations
.
Cancer Cell
.
2018
;
34
(
2
):
225
-
241.e8
.
64.
Basiorka
AA
,
McGraw
KL
,
Eksioglu
EA
, et al
.
The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype
.
Blood
.
2016
;
128
(
25
):
2960
-
2975
.
65.
Vainchenker
W
,
Kralovics
R
.
Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms
.
Blood
.
2017
;
129
(
6
):
667
-
679
.
66.
Tefferi
A
.
Primary myelofibrosis: 2019 update on diagnosis, risk-stratification and management
.
Am J Hematol
.
2018
;
93
(
12
):
1551
-
1560
.
67.
Kramann
R
,
Schneider
RK
.
The identification of fibrosis-driving myofibroblast precursors reveals new therapeutic avenues in myelofibrosis
.
Blood
.
2018
;
131
(
19
):
2111
-
2119
.
You do not currently have access to this content.

Comments

0 Comments