Background
Materials and methods
Patients
Gene-expression profiling
Statistical analysis
Results
Association of miR-363 level with clinico-molecular properties
Characteristic | Chemotherapy group | Allo-HSCT group | ||||
---|---|---|---|---|---|---|
High miR-363 (n = 45) | Low miR-363 (n = 45) |
P
| High miR-363 (n = 36) | Low miR-363 (n = 36) |
P
| |
Age/years, median | 68 (33–88) | 62 (22–77) | 0.005 | 52 (18–65) | 51 (21–72) | 0.585 |
Age group, n (%), years | 0.006 | 0.793 | ||||
< 60 | 8 (17.8) | 21 (46.7) | 25 (69.4) | 27 (75.0) | ||
≥ 60 | 37 (82.2) | 24 (53.3) | 11 (30.6) | 9 (25.0) | ||
Gender, n (%) | 1.000 | 0.634 | ||||
Male | 25 (55.6) | 25 (55.6) | 22 (55.6) | 19 (52.8) | ||
Female | 20 (44.4) | 20 (44.4) | 14 (38.9) | 17 (47.2) | ||
WBC, × 109/L, median | 8.3 (0.7–171.9) | 39.8 (2.5–298.4) | 0.001 | 11.4 (0.6–77.3) | 35.8 (1.2–223.8) | 0.001 |
BM blast (%), median | 71 (30–98) | 73 (32–99) | 0.580 | 67.5 (30–95) | 71.5 (39–100) | 0.156 |
PB blast (%), median | 16 (0–91) | 52 (0–98) | 0.007 | 33.5 (0–90) | 56 (8–96) | 0.008 |
FAB subtypes, n (%) | ||||||
M0 | 5 (11.1) | 3 (6.7) | 0.714 | 7 (19.4) | 2 (5.6) | 0.151 |
M1 | 9 (20) | 11 (24.4) | 0.800 | 10 (37.8) | 13 (36.1) | 0.614 |
M2 | 10 (22.2) | 11 (24.4) | 1.000 | 9 (25.0) | 10 (27.8) | 1.000 |
M4 | 10 (22.2) | 14 (31.1) | 0.475 | 5 (13.9) | 9 (25.0) | 0.372 |
M5 | 8 (17.8) | 5 (11.1) | 0.550 | 3 (8.3) | 1 (2.8) | 0.614 |
M6 | 2 (4.4) | 1 (2.2) | 1.000 | 1 (2.8) | 0 | 1.000 |
M7 | 1 (2.2) | 0 (0) | 1.000 | 1 (2.8) | 0 | 1.000 |
Others | 1 (2.2) | 0 (0) | 1.000 | 0 | 1 (2.8) | 1.000 |
Karyotype, n (%) | ||||||
Normal | 20 (44.4) | 24 (53.3) | 0.527 | 16 (44.4) | 18 (50.0) | 0.814 |
Complex | 11 (24.4) | 1 (2.2) | 0.004 | 11 (30.6) | 1 (2.8) | 0.003 |
8 Trisomy | 0 | 2 (4.4) | 0.494 | 2 (5.6) | 5 (13.9) | 0.429 |
CBFβ–MYH11 | 0 | 7 (15.6) | 0.012 | 0 | 5 (13.9) | 0.054 |
11q23/MLL | 4 (8.9) | 1 (2.2) | 0.361 | 2 (5.6) | 1 (2.8) | 1.000 |
−7/7q− | 2 (4.4) | 1 (2.2) | 1.000 | 1 (2.8) | 1 (2.8) | 1.000 |
BCR–ABL1 | 1 (2.2) | 0 | 1.000 | 1 (2.8) | 1 (2.8) | 1.000 |
RUNX1–RUNX1T | 1 (2.2) | 5 (11.1) | 0.203 | 0 | 1 (2.8) | 1.000 |
Others | 6 (13.3) | 4 (8.9) | 0.739 | 3 (8.3) | 3 (8.3) | 1.000 |
Risk, n (%) | ||||||
Good | 1 (2.2) | 12 (26.7) | 0.002 | 0 | 6 (16.7) | 0.025 |
Intermediate | 25 (55.6) | 25 (55.6) | 1.000 | 19 (52.8) | 22 (61.1) | 0.634 |
Poor | 18 (40.0) | 7 (15.6) | 0.018 | 17 (47.2) | 7 (19.4) | 0.023 |
Others | 1 (2.2) | 1 (2.2) | 1.000 | 0 | 1 (2.8) | 1.000 |
FLT3–ITD, n (%) | 0.784 | 0.045 | ||||
Presence | 7 (15.6) | 9 (20.0) | 4 (11.1) | 12 (33.3) | ||
Absence | 38 (84.4) | 36 (80.0) | 32 (88.9) | 24 (66.7) | ||
NPM1, n (%) | 0.023 | 0.430 | ||||
Mutation | 9 (20.0) | 20 (44.4) | 8 (22.2) | 12 (33.3) | ||
Wild type | 36 (80.0) | 25 (55.6) | 28 (77.8) | 24 (66.7) | ||
CEBPA, n (%) | ||||||
Single mutation | 1 (2.2) | 2 (4.4) | 1.000 | 0 | 5 (13.9) | 0.054 |
Double mutation | 0 | 0 | 1 (2.8) | 2 (5.6) | 1.000 | |
Wild type | 44 (97.8) | 43 (95.6) | 1.000 | 35 (97.2) | 29 (80.6) | 0.055 |
DNMT3A, n (%) | 1000 | 0.786 | ||||
Mutation | 13 (28.9) | 12 (26.7) | 10 (27.8) | 8 (22.2) | ||
Wild type | 32 (71.1) | 33 (73.3) | 26 (72.2) | 28 (7.8) | ||
IDH1/IDH2, n (%) | 0.167 | 0.415 | ||||
Mutation | 5 (11.1) | 11 (24.4) | 11 (30.6) | 7 (19.4) | ||
Wild type | 40 (88.9) | 34 (75.6) | 25 (69.4) | 29 (80.6) | ||
RUNX1, n (%) | 0.714 | 0.260 | ||||
Mutation | 5 (11.1) | 3 (6.7) | 6 (16.7) | 2 (5.6) | ||
Wild type | 40 (88.9) | 42 (93.3) | 30 (83.3) | 34 (94.4) | ||
MLL–PTD, n (%) | 1.000 | 0.614 | ||||
Presence | 2 (4.4) | 3 (6.7) | 3 (8.3) | 1 (2.8) | ||
Absence | 43 (95.6) | 42 (93.7) | 33 (91.7) | 35 (97.2) | ||
NRAS/KRAS, n (%) | 1.000 | 1.000 | ||||
Mutation | 6 (13.3) | 7 (15.6) | 4 (11.1) | 3 (8.3) | ||
Wild type | 39 (86.7) | 38 (84.4) | 32 (88.9) | 33 (91.7) | ||
TET2, n (%) | 0.118 | 0.614 | ||||
Mutation | 9 (20.0) | 3 (6.7) | 1 (2.8) | 3 (8.3) | ||
Wild type | 36 (80.0) | 42 (93.7) | 35 (97.2) | 33 (91.7) | ||
TP53, n (%) | 0.000 | 0.115 | ||||
Mutation | 11 (24.4) | 0 | 4 (11.1) | 0 | ||
Wild type | 34 (75.6) | 45 (100.0) | 32 (88.9) | 36 (100.0) | ||
Relapse, n (%) | 0.001 | 0.474 | ||||
Yes | 42 (93.3) | 28 (62.2) | 23 (63.9) | 19 (47.2) | ||
No | 3 (6.7) | 17 (37.8) | 13 (36.1) | 17 (52.8) |
Prognostic value of miR-363 expression in patients treated with chemotherapy or allo-HSCT
MiR-363 is associated with clinical outcome in AML
Variables | EFS | OS | ||
---|---|---|---|---|
HR (95% CI) | P-value | HR (95% CI) | P-value | |
Univariate analyses | ||||
MiR-363 (high vs. low) | 2.224 (1.369–3.612) | 0.001 | 2.389 (1.468–3.887) | 0.000 |
WBC (≥ 20 vs. < 20 × 109/L) | 1.015 (0.633–1.627) | 0.952 | 0.980 (0.611–1.571) | 0.932 |
FLT3–ITD (positive vs. negative) | 1.095 (0.587–2.040) | 0.776 | 1.049 (0.563–1.956) | 0.880 |
NPM1 (mutated vs. wild) | 1.050 (0.633–1.741) | 0.850 | 0.965 (0.582–1.599) | 0.890 |
DNMT3A (mutated vs. wild) | 1.301 (0.774–2.185) | 0.320 | 1.299 (0.775–2.179) | 0.321 |
RUNX1 (mutated vs. wild) | 1.502 (0.717–3.147) | 0.281 | 1.591 (0.759–3.335) | 0.219 |
TP53 (mutated vs. wild) | 3.011 (1.539–5.892) | 0.001 | 2.898 (1.487–5.649) | 0.002 |
TET2 (mutated vs. wild) | 0.778 (0.372–1.625) | 0.504 | 0.686 (0.328–1.434) | 0.316 |
MLL–PTD (mutated vs. wild) | 0.891 (0.324–2.445) | 0.822 | 0.945 (0.344–2.596) | 0.913 |
IDH1/IDH2 (mutated vs. wild) | 0.973 (0.271–1.273) | 0.926 | 0.988 (0.550–1.777) | 0.969 |
NRAS/KRAS (mutated vs. wild) | 1.214 (0.637–2.314) | 0.556 | 1.228 (0.644–2.340) | 0.532 |
Multivariate analyses | ||||
MiR-363 (high vs. low) | 2.362 (1.346–4.145) | 0.003 | 2.683 (1.507–4.779) | 0.001 |
WBC (≥ 20 vs. < 20 × 109/L) | 1.806 (1.036–3.151) | 0.037 | 1.861 (1.056–3.280) | 0.032 |
RUNX1 (mutated vs. wild) | 1.706 (0.797–3.654) | 0.169 | 1.819 (0.850–3.892) | 0.123 |
TP53 (mutated vs. wild) | 2.786 (1.312–5.915) | 0.008 | 2.566 (1.221–5.395) | 0.013 |
Variables | EFS | OS | ||
---|---|---|---|---|
HR (95% CI) | P-value | HR (95% CI) | P-value | |
Univariate analyses | ||||
MiR-363 (high vs. low) | 1.182 (0.643–2.175) | 0.590 | 1.424 (0.775–2.619) | 0.255 |
WBC (≥ 20 vs. < 20 × 109/L) | 1.089 (0.594–1.999) | 0.782 | 0.826 (0.450–1.516) | 0.537 |
FLT3–ITD (positive vs. negative) | 1.876 (0.914–3.851) | 0.086 | 1.973 (0.953–4.084) | 0.067 |
NPM1 (mutated vs. wild) | 1.007 (0.515–1.970) | 0.983 | 1.023 (0.523–1.998) | 0.948 |
DNMT3A (mutated vs. wild) | 1.285 (0.655–2.520) | 0.466 | 1.387 (0.704–2.731) | 0.344 |
RUNX1 (mutated vs. wild) | 1.145 (0.449–2.290) | 0.777 | 1.579 (0.613–4.067) | 0.344 |
TP53 (mutated vs. wild) | 2.034 (0.718–5.760) | 0.181 | 4.334 (1.453–12.925) | 0.009 |
TET2 (mutated vs. wild) | 0.526 (0.127–2.186) | 0.377 | 0.670 (0.162–2.776) | 0.581 |
MLL–PTD (mutated vs. wild) | 5.775 (1.664–20.042) | 0.006 | 2.728 (0.832–8.944) | 0.098 |
IDH1/IDH2 (mutated vs. wild) | 0.587 (0.271–1.273) | 0.177 | 0.633 (0.293–1.368) | 0.245 |
NRAS/KRAS (mutated vs. wild) | 0.796 (0.245–2.586) | 0.705 | 0.488 (0.150–1.587) | 0.233 |
Multivariate analyses | ||||
MLL–PTD (mutated vs. wild) | 5.180 (1.449–18.511) | 0.011 | 3.136 (0.943–10.429) | 0.062 |
FLT3–ITD (positive vs. negative) | 1.837 (0.868–3.888) | 0.112 | 2.301 (1.090–4.860) | 0.029 |
TP53 (mutated vs. wild) | 2.493 (0.860–7.226) | 0.092 | 5.848 (1.885–18.142) | 0.002 |
Allo-HSCT overcomes the adverse prognostic role of miR-363 expression
Biological insight of miR-363 expression in AML
GO ID | GO terms | Percentage of members of the GO term present in the miR-363 profile | P-value |
---|---|---|---|
GO:0050789 | Regulation of biological process | 69.5 | < 0.001 |
GO:0050794 | Regulation of cellular process | 64.4 | < 0.001 |
GO:0051716 | Cellular response to stimulus | 44.1 | 0.009 |
GO:0007154 | Cell communication | 40.7 | 0.009 |
GO:0032502 | Developmental process | 39.0 | 0.002 |
GO:0007275 | Multicellular organism development | 37.3 | < 0.001 |
GO:0048731 | System development | 33.9 | < 0.001 |
GO:0048869 | Cellular developmental process | 29.4 | 0.003 |
GO:0030154 | Cell differentiation | 28.2 | 0.001 |
GO:0042221 | Response to chemical | 27.7 | 0.025 |
GO:0010033 | Response to organic substance | 20.3 | 0.026 |
GO:0070887 | Cellular response to chemical stimulus | 19.8 | 0.018 |
GO:0009605 | Response to external stimulus | 16.9 | 0.009 |
GO:0045595 | Regulation of cell differentiation | 15.3 | 0.001 |
GO:0006955 | Immune response | 13.6 | 0.012 |