1. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 20025, China 2. CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
In patients with acute promyelocytic leukemia (APL), intracranial hemorrhage (ICH), if not identified promptly, could be fatal. It is the leading cause of failure of induction and early death. Thus, biomarkers that could promptly predict severe complications are critical. Here, cytokine differences between patients with APL with and without ICH were investigated to develop predictive models for this complication. The initial cytokine profiling using plasma samples from 39 patients and 18 healthy donors found a series of cytokines that were remarkedly different between patients with APL and healthy controls. The APL patients were subsequently divided into high and low white blood cell count groups. Results showed that tumor necrosis factor α and interleukin 8 (IL-8) were vital in distinguishing patients with APL who did or did not develop ICH. In addition, verification in 81 patients with APL demonstrated that the two cytokines were positively correlated with the cumulative incidence of ICH. Finally, in-vitro and in-vivo experimental evidence were provided to show that IL-8 influenced the migration of APL-derived NB4 cells and impaired the blood–brain barrier in PML/RARα positive blast-transplanted FVB/NJ mice. These assessments may facilitate the early warning of ICH and reduce future mortality levels in APL.
All patients (total= 39)(median (range)/number of patients)
P for single factor analysis
P for multiple factor analysis
HR (95% CI)
ICH (n = 15)
non-ICH (n = 24)
Age, year
36 (16−66)
33 (16−70)
0.831
Gender, n (%)
0.734
Male
9 (60)
15 (62.5)
Female
6 (40)
9 (37.5)
WBC count (grouped), n (%)
0.508
Low (< 10 × 109)
7 (46.67)
15 (62.5)
High (≥ 10 × 109)
8 (53.33)
9 (37.5)
Leucocyte count, × 109/L
33.51 (0.79−152.54)
2.39 (0.8−115.68)
0.058
0.492
1.36 (0.29−6.41)
Hemoglobin, g/L
77 (31−135)
85.5 (60−137)
0.323
Platelet count, × 109/L
18 (8.2−98)
31 (14−118)
0.028
0.925
0.83 (0.13−5.18)
APTT, s
29.4 (23.5−41.3)
28.4 (21.4−39.1)
0.415
PT, s
16 (11.3−24)
13.35 (11.7−18.6)
0.081
0.678
0.73 (0.1−5.41)
INR
1.36 (0.93−1.82)
1.23 (0.9−1.61)
0.058
0.788
1.63 (0.19−13.7)
Fg, g/L
1 (0.4−1.9)
1.5 (0.4−3.1)
0.038
0.17
0.62 (0.13−3.02)
D-dimer, mg/L
9.7 (4.73–45.1)
6.04 (0.65–73.87)
0.035
0.567
1.4 (0.4–3.04)
Lactic dehydrogenase, U/L
374 (126−1460)
227 (80−4402)
0.123
0.017
3.62 (1.26–10.42)
BM blast (%)
92 (81−98)
88 (26−97)
0.003
0.093
1.18 (1−1.4)
PB blast (%)
81 (4−96)
66.5 (3−94)
0.191
0.843
0.99 (0.96−1.02)
APTT, activated partial thromboplastin time; Fg, fibrinogen; LDH, lactic dehydrogenase; BM, bone marrow; PB, peripheral blood; PR, PML-RARα.The bold-faced number indicates statistical significance for analysis.
Tab.1
Cytokines (pg/mL)
Healthy controls (n = 18)(median (range))
Patients with APL (n = 39)(median (range))
P value
Basic FGF
2.39 (1.07−3.95)
29.1 (1.97−253.93)
< 0.001
CTACK
5.11 (2.8−10.22)
585.11 (243.35−2877.1)
< 0.001
Eotaxin
33.72 (8.63−55.5)
56.6 (21.29−177.12)
< 0.001
G-CSF
52.01 (9.07−85.56)
275.56 (113.91−7611.97)
< 0.001
GROα
45.42 (33.18−60.06)
516.44 (189.03−10 079.31)
< 0.001
HGF
247.66 (174.53−393.93)
3761.7 (529.4−72 585.02)
< 0.001
IFNγ
33.56 (14−62)
57.71 (19.57−225.62)
0.02
IL-1α
0 (0−0)
53.28 (19.57−150.54)
< 0.001
IL-1β
0 (0−1.77)
3.15 (0.97−69.81)
< 0.001
IL-10
0 (0−0)
10.48 (0.67−485.56)
< 0.001
IL-12(p70)
23.02 (10.39−55.65)
3.63 (0.93−145.74)
< 0.001
IL-13
0 (0−0.18)
0.46 (0.18−26.73)
< 0.001
IL-15
7.66 (2.06−10.86)
45.26 (6.16−1039.94)
0.137
IL-16
316.26 (91.93−518.35)
209.42 (48.75−4309.43)
0.287
IL-17
18.18 (4.77−81.27)
9.41 (4.77−190.99)
0.661
IL-18
58.99 (35.62−83.1)
65.8 (19.3−869.38)
0.336
IL-1Rα
138.7 (1.15−284.8)
251.04 (32.94−2359.54)
0.002
IL-2
0 (0−0)
2.82 (0.59−68.16)
< 0.001
IL-2Rα
47.68 (5.47−68.13)
144.31 (55.29−410.42)
< 0.001
IL-3
113.59 (81.26−139.97)
0.46 (0.11−11.29)
< 0.001
IL-5
0 (0−0)
25.2 (1.82−268.49)
< 0.001
IL-6
2.39 (1.01−4)
8.89 (2.06−126.56)
< 0.001
IL-8
9.34 (7.37−10.9)
93.92 (20.75−2118.03)
< 0.001
IL-9
36.88 (11.17−49.23)
39.04 (13.71−1745.51)
0.064
IP-10
333.26 (308.08−360.86)
754.46 (259.77−1933.17)
< 0.001
LIF
0 (0−0)
8.07 (2.11−515.68)
< 0.001
M-CSF
0 (0−0)
45.82 (26.27−173.27)
< 0.001
MCP-1
18.6 (11.02−21.94)
300.49 (26.2−843.85)
< 0.001
MIF
107.05 (83−128.74)
4578.01 (522.25−2 281 950)
< 0.001
MIG
905.23 (803.15−996.64)
714.58 (233.36−2577.87)
0.002
MIP-1β
34.92 (26.48−41.85)
75.1 (23.4−470.42)
< 0.001
PDGF-BB
942.4 (704.7−1089.1)
142.23 (67.41−2251.54)
< 0.001
RANTES
3.13 (2.07−3.98)
795.17 (54.21−15 337.05)
< 0.001
SCF
86.87 (68.55−110.14)
104.17 (37.77−202.57)
0.02
SCGFβ
33.62 (25.29−40.01)
741 584.86 (332 390.63−880 067.1)
< 0.001
SDF-1α
55.96 (13.4−94.5)
683.19 (195.57−1476.55)
< 0.001
TNFα
0 (0−0)
38.83 (10.41−328.32)
< 0.001
TNFβ
0 (0−0)
4.34 (0.25−108.2)
< 0.001
TRAIL
108.36 (89.49−129.95)
61.6 (21.31−173.42)
< 0.001
VEGF
24.18 (16.25−30.84)
361.78 (198.72−1040.59)
< 0.001
β-NGF
1.89 (1.08−2.89)
1.8 (0.26−113.03)
0.959
Tab.2
Fig.1
Groups
Ranking
Measure 1
Measure 2
Measure 3
Measure 4
Low WBC count group
1
MIP-1β
TNFα
TNFα
TNFα
2
TNFα
MIP-1β
MIP-1β
MIP-1β
3
RANTES
IL-2Rα
RANTES
IL-2Rα
4
IL-2Rα
RANTES
IL-2Rα
RANTES
5
MIG
TRAIL
GROα
GROα
High WBC count group
1
IL-8
IL-8
IL-8
MCP-1
2
MCP-1
Basic FGF
MCP-1
IL-8
3
Basic FGF
MCP-1
Basic FGF
TNFα
4
SDF-1α
MIF
SDF-1α
Basic FGF
5
TNFα
SCGFβ
TNFα
SCF
Tab.3
Fig.2
Fig.3
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