Key Points

  • NOTCH/PI3K-AKT signaling axis and cell cycle regulators are the key players that drive T-LBL.

  • Mutations in KMT2D, an epigenetic modifier, are associated with poor prognosis in T-LBL.

Abstract

T-cell lymphoblastic lymphoma (T-LBL) is a heterogeneous malignancy of lymphoblasts committed to T-cell lineage. The dismal outcomes (15%-30%) after T-LBL relapse warrant establishing risk-based treatment. To our knowledge, this study presents the first comprehensive, systematic, integrated, genome-wide analysis including relapsed cases that identifies molecular markers of prognostic relevance for T-LBL. NOTCH1 was identified as the putative driver for T-LBL. An activated NOTCH/PI3K-AKT signaling axis and alterations in cell cycle regulators constitute the core oncogenic program for T-LBL. Mutated KMT2D was identified as a prognostic marker. The cumulative incidence of relapse was 47% ± 17% in patients with KMT2D mutations, compared with 14% ± 3% in wild-type KMT2D. Structural analysis of the mutated domains of KMT2D revealed a plausible impact on structure and functional consequences. These findings provide new insights into the pathogenesis of T-LBL, including high translational potential. The ongoing LBL 2018 trial (www.clinicaltrials.gov #NCT04043494) allows for prospective validation and subsequent fine tuning of the stratification criteria for T-LBL risk groups to improve survival of pediatric patients.

REFERENCES

1.
Basso
K
,
Mussolin
L
,
Lettieri
A
, et al
.
T-cell lymphoblastic lymphoma shows differences and similarities with T-cell acute lymphoblastic leukemia by genomic and gene expression analyses
.
Genes Chromosomes Cancer
.
2011
;
50
(
12
):
1063
-
1075
.
2.
Raetz
EA
,
Perkins
SL
,
Bhojwani
D
, et al
.
Gene expression profiling reveals intrinsic differences between T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma
.
Pediatr Blood Cancer
.
2006
;
47
(
2
):
130
-
140
.
3.
Burkhardt
B
.
Paediatric lymphoblastic T-cell leukaemia and lymphoma: one or two diseases?
Br J Haematol
.
2010
;
149
(
5
):
653
-
668
.
4.
Van Vlierberghe
P
,
Ferrando
A
.
The molecular basis of T cell acute lymphoblastic leukemia
.
J Clin Invest
.
2012
;
122
(
10
):
3398
-
3406
.
5.
Weng
AP
,
Ferrando
AA
,
Lee
W
, et al
.
Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia
.
Science
.
2004
;
306
(
5694
):
269
-
271
.
6.
Breit
S
,
Stanulla
M
,
Flohr
T
, et al
.
Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia
.
Blood
.
2006
;
108
(
4
):
1151
-
1157
.
7.
Park
MJ
,
Taki
T
,
Oda
M
, et al
.
FBXW7 and NOTCH1 mutations in childhood T cell acute lymphoblastic leukaemia and T cell non-Hodgkin lymphoma
.
Br J Haematol
.
2009
;
145
(
2
):
198
-
206
.
8.
Larson Gedman
A
,
Chen
Q
,
Kugel Desmoulin
S
, et al
.
The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: a report from the Children’s Oncology Group
.
Leukemia
.
2009
;
23
(
8
):
1417
-
1425
.
9.
Clappier
E
,
Collette
S
,
Grardel
N
, et al;
EORTC-CLG
.
NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951
.
Leukemia
.
2010
;
24
(
12
):
2023
-
2031
.
10.
Zuurbier
L
,
Homminga
I
,
Calvert
V
, et al
.
NOTCH1 and/or FBXW7 mutations predict for initial good prednisone response but not for improved outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on DCOG or COALL protocols
.
Leukemia
.
2010
;
24
(
12
):
2014
-
2022
.
11.
Kox
C
,
Zimmermann
M
,
Stanulla
M
, et al
.
The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL patients treated on the ALL-BFM 2000 protocol can be separated from FBXW7 loss of function
.
Leukemia
.
2010
;
24
(
12
):
2005
-
2013
.
12.
Erbilgin
Y
,
Sayitoglu
M
,
Hatirnaz
O
, et al
.
Prognostic significance of NOTCH1 and FBXW7 mutations in pediatric T-ALL
.
Dis Markers
.
2010
;
28
(
6
):
353
-
360
.
13.
Mansur
MB
,
Hassan
R
,
Barbosa
TC
, et al
.
Impact of complex NOTCH1 mutations on survival in paediatric T-cell leukaemia
.
BMC Cancer
.
2012
;
12
(
1
):
9
.
14.
Jenkinson
S
,
Koo
K
,
Mansour
MR
, et al
.
Impact of NOTCH1/FBXW7 mutations on outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on the MRC UKALL 2003 trial
.
Leukemia
.
2013
;
27
(
1
):
41
-
47
.
15.
Kimura
S
,
Seki
M
,
Yoshida
K
, et al
.
NOTCH1 pathway activating mutations and clonal evolution in pediatric T-cell acute lymphoblastic leukemia
.
Cancer Sci
.
2019
;
110
(
2
):
784
-
794
.
16.
Callens
C
,
Baleydier
F
,
Lengline
E
, et al
.
Clinical impact of NOTCH1 and/or FBXW7 mutations, FLASH deletion, and TCR status in pediatric T-cell lymphoblastic lymphoma
.
J Clin Oncol
.
2012
;
30
(
16
):
1966
-
1973
.
17.
Bonn
BR
,
Rohde
M
,
Zimmermann
M
, et al
.
Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence
.
Blood
.
2013
;
121
(
16
):
3153
-
3160
.
18.
Balbach
ST
,
Makarova
O
,
Bonn
BR
, et al
.
Proposal of a genetic classifier for risk group stratification in pediatric T-cell lymphoblastic lymphoma reveals differences from adult T-cell lymphoblastic leukemia
.
Leukemia
.
2016
;
30
(
4
):
970
-
973
.
19.
Palomero
T
,
Sulis
ML
,
Cortina
M
, et al
.
Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia
.
Nat Med
.
2007
;
13
(
10
):
1203
-
1210
.
20.
Palomero
T
,
Dominguez
M
,
Ferrando
AA
.
The role of the PTEN/AKT Pathway in NOTCH1-induced leukemia
.
Cell Cycle
.
2008
;
7
(
8
):
965
-
970
.
21.
Liu
Y
,
Easton
J
,
Shao
Y
, et al
.
The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia
.
Nat Genet
.
2017
;
49
(
8
):
1211
-
1218
.
22.
Lindqvist
CM
,
Nordlund
J
,
Ekman
D
, et al
.
The mutational landscape in pediatric acute lymphoblastic leukemia deciphered by whole genome sequencing
.
Hum Mutat
.
2015
;
36
(
1
):
118
-
128
.
23.
Ma
X
,
Liu
Y
,
Liu
Y
, et al
.
Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours
.
Nature
.
2018
;
555
(
7696
):
371
-
376
.
24.
Van Vlierberghe
P
,
Ambesi-Impiombato
A
,
De Keersmaecker
K
, et al
.
Prognostic relevance of integrated genetic profiling in adult T-cell acute lymphoblastic leukemia
.
Blood
.
2013
;
122
(
1
):
74
-
82
.
25.
Gutierrez
A
,
Kentsis
A
,
Sanda
T
, et al
.
The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia
.
Blood
.
2011
;
118
(
15
):
4169
-
4173
.
26.
Krieger
D
,
Moericke
A
,
Oschlies
I
, et al
.
Frequency and clinical relevance of DNA microsatellite alterations of the CDKN2A/B, ATM and p53 gene loci: a comparison between pediatric precursor T-cell lymphoblastic lymphoma and T-cell lymphoblastic leukemia
.
Haematologica
.
2010
;
95
(
1
):
158
-
162
.
27.
Zhang
JA
,
Mortazavi
A
,
Williams
BA
,
Wold
BJ
,
Rothenberg
EV
.
Dynamic transformations of genome-wide epigenetic marking and transcriptional control establish T cell identity
.
Cell
.
2012
;
149
(
2
):
467
-
482
.
28.
Morin
RD
,
Johnson
NA
,
Severson
TM
, et al
.
Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin
.
Nat Genet
.
2010
;
42
(
2
):
181
-
185
.
29.
Ford
DJ
,
Dingwall
AK
.
The cancer COMPASS: navigating the functions of MLL complexes in cancer [published correction appears in Cancer Genet. 2019;233-234:102]
.
Cancer Genet
.
2015
;
208
(
5
):
178
-
191
.
30.
Ferrero
S
,
Rossi
D
,
Rinaldi
A
, et al
.
KMT2D mutations and TP53 disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy: a FIL study
.
Haematologica
.
2020
;
105
(
6
):
1604
-
1612
.
31.
Wang
H
,
Zang
C
,
Taing
L
, et al
.
NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers
.
Proc Natl Acad Sci USA
.
2014
;
111
(
2
):
705
-
710
.
32.
Dhar
SS
,
Zhao
D
,
Lin
T
, et al
.
MLL4 Is Required to Maintain Broad H3K4me3 Peaks and Super-Enhancers at Tumor Suppressor Genes
.
Mol Cell
.
2018
;
70
(
5
):
825
-
841 e826
.
33.
Hu
D
,
Gao
X
,
Morgan
MA
,
Herz
HM
,
Smith
ER
,
Shilatifard
A
.
The MLL3/MLL4 branches of the COMPASS family function as major histone H3K4 monomethylases at enhancers
.
Mol Cell Biol
.
2013
;
33
(
23
):
4745
-
4754
.
34.
Bonn
BR
,
Huge
A
,
Rohde
M
, et al
.
Whole exome sequencing hints at a unique mutational profile of paediatric T-cell lymphoblastic lymphoma
.
Br J Haematol
.
2015
;
168
(
2
):
308
-
313
.
35.
Li
Z
,
Song
Y
,
Zhang
Y
, et al
.
Genomic and outcome analysis of adult T-cell lymphoblastic lymphoma
.
Haematologica
.
2020
;
105
(
3
):
e107
-
e110
.
36.
Haider
Z
,
Landfors
M
,
Golovleva
I
, et al
.
DNA methylation and copy number variation profiling of T-cell lymphoblastic leukemia and lymphoma
.
Blood Cancer J
.
2020
;
10
(
4
):
45
.
37.
Burkhardt
B
,
Bruch
J
,
Zimmermann
M
, et al
.
Loss of heterozygosity on chromosome 6q14-q24 is associated with poor outcome in children and adolescents with T-cell lymphoblastic lymphoma
.
Leukemia
.
2006
;
20
(
8
):
1422
-
1429
.
38.
Reiter
A
,
Schrappe
M
,
Ludwig
WD
, et al
.
Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report
.
Blood
.
2000
;
95
(
2
):
416
-
421
.
39.
Zhou
W
,
Laird
PW
,
Shen
H
.
Comprehensive characterization, annotation and innovative use of Infinium DNA methylation BeadChip probes
.
Nucleic Acids Res
.
2017
;
45
(
4
):
e22
.
40.
Rohde
M
,
Bonn
BR
,
Zimmermann
M
, et al
.
Multiplex ligation-dependent probe amplification validates LOH6q analyses and enhances insight into chromosome 6q aberrations in pediatric T-cell lymphoblastic leukemia and lymphoma
.
Leuk Lymphoma
.
2015
;
56
(
6
):
1884
-
1887
.
41.
Derrieux
C
,
Trinquand
A
,
Bruneau
J
, et al
.
A Single-Tube, EuroClonality-Inspired, TRG Clonality Multiplex PCR Aids Management of Patients with Enteropathic Diseases, including from Formaldehyde-Fixed, Paraffin-Embedded Tissues
.
J Mol Diagn
.
2019
;
21
(
1
):
111
-
122
.
42.
Fine
JP
,
Gray
RJ
.
A Proportional Hazards Model for the Subdistribution of a Competing Risk
.
J Am Stat Assoc
.
1999
;
94
(
446
):
496
-
509
.
43.
Peng
K
,
Radivojac
P
,
Vucetic
S
,
Dunker
AK
,
Obradovic
Z
.
Length-dependent prediction of protein intrinsic disorder
.
BMC Bioinformatics
.
2006
;
7
(
1
):
208
.
44.
Kelley
LA
,
Mezulis
S
,
Yates
CM
,
Wass
MN
,
Sternberg
MJE
.
The Phyre2 web portal for protein modeling, prediction and analysis
.
Nat Protoc
.
2015
;
10
(
6
):
845
-
858
.
45.
García-Alai
MM
,
Allen
MD
,
Joerger
AC
,
Bycroft
M
.
The structure of the FYR domain of transforming growth factor beta regulator 1
.
Protein Sci
.
2010
;
19
(
7
):
1432
-
1438
.
46.
Zhang
Y
,
Mittal
A
,
Reid
J
,
Reich
S
,
Gamblin
SJ
,
Wilson
JR
.
Evolving Catalytic Properties of the MLL Family SET Domain
.
Structure
.
2015
;
23
(
10
):
1921
-
1933
.
47.
Johnson
A
,
Severson
E
,
Gay
L
, et al
.
Comprehensive Genomic Profiling of 282 Pediatric Low- and High-Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures
.
Oncologist
.
2017
;
22
(
12
):
1478
-
1490
.
48.
Lawrence
MS
,
Stojanov
P
,
Polak
P
, et al
.
Mutational heterogeneity in cancer and the search for new cancer-associated genes
.
Nature
.
2013
;
499
(
7457
):
214
-
218
.
49.
Huang
W
,
Sherman
BT
,
Lempicki
RA
.
Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists
.
Nucleic Acids Res
.
2009
;
37
(
1
):
1
-
13
.
50.
Oswald
F
,
Rodriguez
P
,
Giaimo
BD
, et al
.
A phospho-dependent mechanism involving NCoR and KMT2D controls a permissive chromatin state at Notch target genes
.
Nucleic Acids Res
.
2016
;
44
(
10
):
4703
-
4720
.
51.
Feng
X
,
Ippolito
GC
,
Tian
L
, et al
.
Foxp1 is an essential transcriptional regulator for the generation of quiescent naive T cells during thymocyte development
.
Blood
.
2010
;
115
(
3
):
510
-
518
.
52.
Shahryari
A
,
Jazi
MS
,
Samaei
NM
,
Mowla
SJ
.
Long non-coding RNA SOX2OT: expression signature, splicing patterns, and emerging roles in pluripotency and tumorigenesis
.
Front Genet
.
2015
;
6
:
196
.
53.
Yang
L
,
Li
Y
,
Bhattacharya
A
,
Zhang
Y
.
PEPD is a pivotal regulator of p53 tumor suppressor
.
Nat Commun
.
2017
;
8
(
1
):
2052
.
54.
Shan
J
,
Liu
Y
,
Wang
Y
,
Li
Y
,
Yu
X
,
Wu
C
.
GALNT14 Involves the Regulation of Multidrug Resistance in Breast Cancer Cells
.
Transl Oncol
.
2018
;
11
(
3
):
786
-
793
.
55.
O’Neil
J
,
Grim
J
,
Strack
P
, et al
.
FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors
.
J Exp Med
.
2007
;
204
(
8
):
1813
-
1824
.
56.
Silva
A
,
Yunes
JA
,
Cardoso
BA
, et al
.
PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability
.
J Clin Invest
.
2008
;
118
(
11
):
3762
-
3774
.
57.
Shan
X
,
Czar
MJ
,
Bunnell
SC
, et al
.
Deficiency of PTEN in Jurkat T cells causes constitutive localization of Itk to the plasma membrane and hyperresponsiveness to CD3 stimulation
.
Mol Cell Biol
.
2000
;
20
(
18
):
6945
-
6957
.
58.
Zuurbier
L
,
Petricoin
EF
III
,
Vuerhard
MJ
, et al
.
The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia
.
Haematologica
.
2012
;
97
(
9
):
1405
-
1413
.
59.
Bandapalli
OR
,
Schuessele
S
,
Kunz
JB
, et al
.
The activating STAT5B N642H mutation is a common abnormality in pediatric T-cell acute lymphoblastic leukemia and confers a higher risk of relapse
.
Haematologica
.
2014
;
99
(
10
):
e188
-
e192
.
60.
Zhang
W
,
Liang
X
,
Gong
Y
,
Xiao
C
,
Guo
B
,
Yang
T
.
The Signal Transducer and Activator of Transcription 5B (STAT5B) Gene Promotes Proliferation and Drug Resistance of Human Mantle Cell Lymphoma Cells by Activating the Akt Signaling Pathway
.
Med Sci Monit
.
2019
;
25
:
2599
-
2608
.
61.
Küçük
C
,
Jiang
B
,
Hu
X
, et al
.
Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells
.
Nat Commun
.
2015
;
6
(
1
):
6025
.
62.
Kontro
M
,
Kuusanmäki
H
,
Eldfors
S
, et al
.
Novel activating STAT5B mutations as putative drivers of T-cell acute lymphoblastic leukemia
.
Leukemia
.
2014
;
28
(
8
):
1738
-
1742
.
63.
Gouilleux-Gruart
V
,
Gouilleux
F
,
Desaint
C
, et al
.
STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients
.
Blood
.
1996
;
87
(
5
):
1692
-
1697
.
64.
Zhang
Q
,
Nowak
I
,
Vonderheid
EC
, et al
.
Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome
.
Proc Natl Acad Sci USA
.
1996
;
93
(
17
):
9148
-
9153
.
65.
Greenplate
A
,
Wang
K
,
Tripathi
RM
, et al
.
Genomic profiling of T-cell neoplasms reveals frequent JAK1 and JAK3 mutations with clonal evasion from targeted therapies
.
JCO Precis Oncol
.
2018
;PO.17.00019.
66.
Li
Y
,
Buijs-Gladdines
JG
,
Canté-Barrett
K
, et al
.
IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study
.
PLoS Med
.
2016
;
13
(
12
):
e1002200
.
67.
Lin
JX
,
Mietz
J
,
Modi
WS
,
John
S
,
Leonard
WJ
.
Cloning of human Stat5B. Reconstitution of interleukin-2-induced Stat5A and Stat5B DNA binding activity in COS-7 cells
.
J Biol Chem
.
1996
;
271
(
18
):
10738
-
10744
.
68.
Gröbner
SN
,
Worst
BC
,
Weischenfeldt
J
, et al;
ICGC MMML-Seq Project
.
The landscape of genomic alterations across childhood cancers
.
Nature
.
2018
;
555
(
7696
):
321
-
327
.
69.
Vainchenker
W
,
Constantinescu
SN
.
JAK/STAT signaling in hematological malignancies
.
Oncogene
.
2013
;
32
(
21
):
2601
-
2613
.
70.
Yokoyama
K
,
Yokoyama
N
,
Izawa
K
, et al
.
In vivo leukemogenic potential of an interleukin 7 receptor α chain mutant in hematopoietic stem and progenitor cells
.
Blood
.
2013
;
122
(
26
):
4259
-
4263
.
71.
Landmann
E
,
Burkhardt
B
,
Zimmermann
M
, et al
.
Results and conclusions of the European Intergroup EURO-LB02 trial in children and adolescents with lymphoblastic lymphoma
.
Haematologica
.
2017
;
102
(
12
):
2086
-
2096
.
72.
Baleydier
F
,
Decouvelaere
AV
,
Bergeron
J
, et al
.
T cell receptor genotyping and HOXA/TLX1 expression define three T lymphoblastic lymphoma subsets which might affect clinical outcome
.
Clin Cancer Res
.
2008
;
14
(
3
):
692
-
700
.
73.
Rao
RC
,
Dou
Y
.
Hijacked in cancer: the KMT2 (MLL) family of methyltransferases
.
Nat Rev Cancer
.
2015
;
15
(
6
):
334
-
346
.
74.
Wang
J
,
Muntean
AG
,
Wu
L
,
Hess
JL
.
A subset of mixed lineage leukemia proteins has plant homeodomain (PHD)-mediated E3 ligase activity
.
J Biol Chem
.
2012
;
287
(
52
):
43410
-
43416
.
75.
Liu
Y
,
Qin
S
,
Chen
TY
, et al
.
Structural insights into trans-histone regulation of H3K4 methylation by unique histone H4 binding of MLL3/4
.
Nat Commun
.
2019
;
10
(
1
):
36
.
76.
Dhar
SS
,
Lee
SH
,
Kan
PY
, et al
.
Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4
.
Genes Dev
.
2012
;
26
(
24
):
2749
-
2762
.
77.
Zhang
Y
,
Jang
Y
,
Lee
JE
, et al
.
Selective binding of the PHD6 finger of MLL4 to histone H4K16ac links MLL4 and MOF
.
Nat Commun
.
2019
;
10
(
1
):
2314
.
78.
Li
B
,
Brady
SW
,
Ma
X
, et al
.
Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia
.
Blood
.
2020
;
135
(
1
):
41
-
55
.
79.
Giaimo
BD
,
Oswald
F
,
Borggrefe
T
.
Dynamic chromatin regulation at Notch target genes
.
Transcription
.
2017
;
8
(
1
):
61
-
66
.
80.
Ma
J
,
Wu
M
.
The indicative effect of Notch1 expression for the prognosis of T-cell acute lymphocytic leukemia: a systematic review
.
Mol Biol Rep
.
2012
;
39
(
5
):
6095
-
6100
.
81.
Lv
S
,
Ji
L
,
Chen
B
, et al
.
Histone methyltransferase KMT2D sustains prostate carcinogenesis and metastasis via epigenetically activating LIFR and KLF4
.
Oncogene
.
2018
;
37
(
10
):
1354
-
1368
.
82.
Toska
E
,
Osmanbeyoglu
HU
,
Castel
P
, et al
.
PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D
.
Science
.
2017
;
355
(
6331
):
1324
-
1330
.
83.
Toska
E
,
Castel
P
,
Chhangawala
S
, et al
.
PI3K Inhibition Activates SGK1 via a Feedback Loop to Promote Chromatin-Based Regulation of ER-Dependent Gene Expression
.
Cell Rep
.
2019
;
27
(
1
):
294
-
306 e295
.
84.
Ferrando
AA
,
Neuberg
DS
,
Staunton
J
, et al
.
Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia
.
Cancer Cell
.
2002
;
1
(
1
):
75
-
87
.
85.
Gutierrez
A
,
Sanda
T
,
Ma
W
, et al
.
Inactivation of LEF1 in T-cell acute lymphoblastic leukemia
.
Blood
.
2010
;
115
(
14
):
2845
-
2851
.
86.
Jang
Y
,
Wang
C
,
Zhuang
L
,
Liu
C
,
Ge
K
.
H3K4 Methyltransferase Activity Is Required for MLL4 Protein Stability
.
J Mol Biol
.
2017
;
429
(
13
):
2046
-
2054
.
87.
Zhang
J
,
Dominguez-Sola
D
,
Hussein
S
, et al
.
Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis
.
Nat Med
.
2015
;
21
(
10
):
1190
-
1198
.
88.
Fagan
RJ
,
Dingwall
AK
.
COMPASS Ascending: Emerging clues regarding the roles of MLL3/KMT2C and MLL2/KMT2D proteins in cancer
.
Cancer Lett
.
2019
;
458
:
56
-
65
.
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