Abstract

We used single-cell genomics to characterize a patient with T-cell acute lymphoblastic leukemia treated in the Children’s Oncology Group AALL0434 trial with poor clinical outcome despite favorable genomic features, identifying a STAT1-mediated interferon-related transcriptional signature and inflammatory microenvironment associated with sensitivity to small-molecule JAK inhibition.

1.
Wood
BL
,
Winter
SS
,
Dunsmore
KP
, et al
.
T-lymphoblastic leukemia (T-ALL) shows excellent outcome, lack of significance of the early thymic precursor (ETP) immunophenotype, and validation of the prognostic value of end-induction minimal residual disease (MRD) in Children’s Oncology Group (COG) Study AALL0434 [abstract]
.
Blood
.
2014
;
124
(
21
):
1
.
2.
Hunger
SP
,
Mullighan
CG
.
Acute lymphoblastic leukemia in children.
.
N Engl J Med
.
2015
;
373
(
16
):
1541
-
1552
.
3.
Maude
SL
,
Dolai
S
,
Delgado-Martin
C
, et al
.
Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia
.
Blood
.
2015
;
125
(
11
):
1759
-
1767
.
4.
Delgado-Martin
C
,
Meyer
LK
,
Huang
BJ
, et al
.
JAK/STAT pathway inhibition overcomes IL7-induced glucocorticoid resistance in a subset of human T-cell acute lymphoblastic leukemias
.
Leukemia
.
2017
;
31
(
12
):
2568
-
2576
.
5.
Chen
C
,
Xu
J
,
Vincent
T
, et al
.
Treatment Resistance in ETP-ALL is associated with progenitor-like arrest state [abstract]
.
Blood
.
2021
;
138
(
suppl 1
):
618
.
6.
Weichselbaum
RR
,
Ishwaran
H
,
Yoon
T
, et al
.
An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer
.
Proc Natl Acad Sci U S A
.
2008
;
105
(
47
):
18490
-
18495
.
7.
Han
H
,
Cho
JW
,
Lee
S
, et al
.
TRRUST v2: an expanded reference database of human and mouse transcriptional regulatory interactions
.
Nucleic Acids Res
.
2018
;
46
(
D1
):
D380
-
D386
.
8.
Pölönen
P
,
Di Giacomo
D
,
Seffernick
AE
, et al
.
The genomic basis of childhood T-lineage acute lymphoblastic leukaemia
.
Nature
.
2024
;
632
(
8027
):
1082
-
1091
.
9.
Waldman
AD
,
Fritz
JM
,
Lenardo
MJ
.
A guide to cancer immunotherapy: from T cell basic science to clinical practice
.
Nat Rev Immunol
.
2020
;
20
(
11
):
651
-
668
.
10.
Pitroda
SP
,
Stack
ME
,
Liu
GF
, et al
.
JAK2 inhibitor SAR302503 abrogates PD-L1 expression and targets therapy-resistant non-small cell lung cancers
.
Mol Cancer Ther
.
2018
;
17
(
4
):
732
-
739
.
11.
Benci
JL
,
Xu
B
,
Qiu
Y
, et al
.
Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade
.
Cell
.
2016
;
167
(
6
):
1540
-
1554.e12
.
12.
Jaramillo
S
,
Hennemann
H
,
Horak
P
, et al
.
Ruxolitinib is effective in the treatment of a patient with refractory T-ALL
.
EJHaem
.
2021
;
2
(
1
):
139
-
142
.
13.
Kołodrubiec
J
,
Kozłowska
M
,
Irga-Jaworska
N
, et al
.
Efficacy of ruxolitinib in acute lymphoblastic leukemia: a systematic review
.
Leuk Res
.
2022
;
121
:
106925
.
14.
Naqvi
K
,
Verstovsek
S
,
Kantarjian
H
,
Ravandi
F
.
A potential role of ruxolitinib in leukemia
.
Expert Opin Investig Drugs
.
2011
;
20
(
8
):
1159
-
1166
.
15.
Verbeke
D
,
Gielen
O
,
Jacobs
K
, et al
.
Ruxolitinib synergizes with dexamethasone for the treatment of T-cell acute lymphoblastic leukemia
.
HemaSphere
.
2019
;
3
(
6
):
e310
.
16.
Senkevitch
E
,
Li
W
,
Hixon
JA
, et al
.
Inhibiting Janus Kinase 1 and BCL-2 to treat T cell acute lymphoblastic leukemia with IL7-Rα mutations
.
Oncotarget
.
2018
;
9
(
32
):
22605
-
22617
.
17.
Lan
Q
,
Peyvandi
S
,
Duffey
N
, et al
.
Type I interferon/IRF7 axis instigates chemotherapy-induced immunological dormancy in breast cancer
.
Oncogene
.
2019
;
38
(
15
):
2814
-
2829
.
18.
Erdal
E
,
Haider
S
,
Rehwinkel
J
,
Harris
AL
,
McHugh
PJ
.
A prosurvival DNA damage-induced cytoplasmic interferon response is mediated by end resection factors and is limited by Trex1
.
Genes Dev
.
2017
;
31
(
4
):
353
-
369
.
19.
Sistigu
A
,
Yamazaki
T
,
Vacchelli
E
, et al
.
Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy
.
Nat Med
.
2014
;
20
(
11
):
1301
-
1309
.
20.
Meyer
SC
,
Keller
MD
,
Chiu
S
, et al
.
CHZ868, a type II JAK2 inhibitor, reverses type I JAK inhibitor persistence and demonstrates efficacy in myeloproliferative neoplasms
.
Cancer Cell
.
2015
;
28
(
1
):
15
-
28
.
21.
Lee
SHR
,
Yang
W
,
Gocho
Y
, et al
.
Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response
.
Nat Med
.
2023
;
29
(
1
):
170
-
179
.
22.
Duarte
CW
,
Willey
CD
,
Zhi
D
, et al
.
Expression signature of IFN/STAT1 signaling genes predicts poor survival outcome in glioblastoma multiforme in a subtype-specific manner
.
PLOS ONE
.
2012
;
7
(
1
):
e29653
.
23.
Khodarev
NN
,
Roach
P
,
Pitroda
SP
, et al
.
STAT1 pathway mediates amplification of metastatic potential and resistance to therapy
.
PLoS ONE
.
2009
;
4
(
6
):
e5821
.
24.
Lo
U
,
Chen
Y
,
Cen
J
, et al
.
The driver role of JAK-STAT signalling in cancer stemness capabilities leading to new therapeutic strategies for therapy- and castration-resistant prostate cancer
.
Clin Transl Med
.
2022
;
12
(
8
):
e978
.
25.
Gower
M
,
Li
X
,
Aguilar-Navarro
AG
, et al
.
An inflammatory state defines a high-risk T-lineage acute lymphoblastic leukemia subgroup
.
Sci Transl Med
.
2025
;
17
(
779
):
eadr2012
.
26.
Courtois
L
,
Cabannes-Hamy
A
,
Kim
R
, et al
.
IL-7 receptor expression is frequent in T-cell acute lymphoblastic leukemia and predicts sensitivity to JAK inhibition
.
Blood
.
2023
;
142
(
2
):
158
-
171
.
27.
Ding
YY
,
Sussman
JH
,
Madden
K
, et al
.
Targeting senescent stemlike subpopulations in Philadelphia chromosome-like acute lymphoblastic leukemia
.
Blood
.
2025
;
145
(
11
):
1195
-
1210
.
28.
Xu
J
,
Chen
C
,
Sussman
JH
, et al
.
A multiomic atlas identifies a treatment-resistant, bone marrow progenitor-like cell population in T cell acute lymphoblastic leukemia
.
Nat Cancer
.
2025
;
6
:
102
-
122
.
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