Background
Methods
Patients
Gene expression profiling
Definition of clinical endpoints and statistical analysis
Results
Associations of miR-425 expression with clinical and molecular features
Characteristic | Chemotherapy group | Allo-HSCT group | ||||
---|---|---|---|---|---|---|
High miR-425 (n = 45) | Low miR-425 (n = 45) |
P
| High miR-425 (n = 36) | Low miR-425 (n = 36) |
P
| |
Age/years, median (range) | 63 (22–88) | 68 (33–83) | 0.138 | 52 (25–72) | 50 (18–69) | 0.450 |
Age group/no. (%), years | 0.652 | 0.793 | ||||
< 60 | 16 (35.6) | 13 (28.9) | 27 (75.0) | 25 (69.4) | ||
≥ 60 | 29 (64.4) | 32 (71.1) | 9 (25.0) | 11 (30.6) | ||
Gender/no. (%) | 0.289 | 1.000 | ||||
Male | 28 (62.2) | 22 (48.9) | 21 (58.3) | 20 (55.6) | ||
Female | 17 (37.8) | 23 (51.1) | 15 (41.7) | 16 (44.4) | ||
WBC/× 109/L, median (range) | 15.2 (0.7–298.4) | 16.9 (1.0–297.4) | 0.589 | 30.3 (1.5–98.8) | 28.3 (0.6–223.8) | 0.978 |
BM blast/ %, median (range) | 67 (30–98) | 75 (37–99) | 0.050 | 68 (30–97) | 76 (35–100) | 0.131 |
PB blast/%, median (range) | 18 (0–71) | 53 (0–98) | 0.002 | 41 (0–85) | 53 (0–96) | 0.116 |
FAB subtypes/no. (%) | ||||||
M0 | 0 (0.0) | 8 (17.8) | 0.006 | 3 (8.3) | 6 (16.7) | 0.478 |
M1 | 7 (15.6) | 13 (28.9) | 0.201 | 8 (22.2) | 15 (41.7) | 0.129 |
M2 | 13 (28.9) | 8 (17.8) | 0.231 | 13 (36.1) | 6 (16.7) | 0.107 |
M4 | 14 (31.1) | 10 (22.2) | 0.340 | 8 (22.2) | 6 (16.7) | 0.767 |
M5 | 9 (20) | 4 (8.9) | 0.230 | 3 (8.3) | 1 (2.8) | 0.614 |
M6 | 0 (0.0) | 1 (2.2) | 1.000 | 1 (2.8) | 0 (0.0) | 1.000 |
M7 | 1 (2.2) | 1 (2.2) | 1.000 | 0 (0.0) | 1 (2.8) | 1.000 |
Others | 1 (2.2) | 0 (0.0) | 1.000 | 0 (0.0) | 1 (2.8) | 1.000 |
Karyotype/no. (%) | ||||||
Normal | 21 (46.7) | 23 (51.1) | 0.833 | 17 (47.2) | 17 (47.2) | 1.000 |
Complex | 5 (11.1) | 7 (15.6) | 0.758 | 5 (13.9) | 7 (19.4) | 0.753 |
MLL rearranged | 2 (4.4) | 1 (2.2) | 1.000 | 2 (5.6) | 1 (2.8) | 1.000 |
CBFβ-MYH11 | 7 (15.6) | 0 (0.0) | 0.012 | 5 (13.9) | 0 (0.0) | 0.054 |
BCR-ABL1 | 1 (2.2) | 0 (0.0) | 1.000 | 1 (2.8) | 1 (2.8) | 1.000 |
RUNX1-RUNX1T | 5 (11.1) | 1 (2.2) | 0.203 | 0 (0.0) | 1 (2.8) | 1.000 |
Others | 4 (8.9) | 13 (28.9) | 0.029 | 6 (16.7) | 9 (25) | 0.563 |
Risk (cyto)/no. (%) | ||||||
Good | 12 (26.7) | 1 (2.2) | 0.002 | 5 (13.9) | 1 (2.8) | 0.199 |
Intermediate | 20 (44.4) | 30 (66.7) | 0.056 | 17 (47.2) | 24 (66.7) | 0.153 |
Poor | 13 (28.9) | 12 (26.7) | 1.000 | 13 (36.1) | 11 (30.6) | 0.803 |
Others | 0 (0.0) | 2 (4.4) | 0.494 | 1 (2.8) | 0 (0.0) | 1.000 |
FLT3-ITD/no. (%) | 1.000 | 0.396 | ||||
Presence | 8 (17.8) | 8 (17.8) | 6 (16.7) | 10 (27.8) | ||
Absence | 37 (82.2) | 37 (82.2) | 30 (83.3) | 26 (72.2) | ||
NPM1/no. (%) | 0.367 | 0.430 | ||||
Presence | 12 (26.7) | 17 (37.8) | 8 (22.2) | 12 (33.3) | ||
Absence | 33 (73.3) | 28 (62.2) | 28 (77.8) | 24 (66.7) | ||
DNMT3A/no. (%) | 0.059 | 0.415 | ||||
Presence | 8 (17.8) | 17 (37.8) | 7 (19.4) | 11 (30.6) | ||
Absence | 37 (82.2) | 28 (62.2) | 29 (80.6) | 25 (69.4) | ||
RUNX1/no. (%) | 0.058 | 1.000 | ||||
Presence | 1 (2.2) | 7 (15.6) | 4 (11.1) | 4 (11.1) | ||
Absence | 44 (97.8) | 38 (84.4) | 32 (88.9) | 32 (88.9) | ||
MLL-PTD/no. (%) | 1.000 | 0.115 | ||||
Presence | 2 (4.4) | 3 (6.7) | 4 (11.1) | 0 (0.0) | ||
Absence | 43 (95.6) | 42 (93.3) | 32 (88.9) | 36 (100.0) | ||
TP53/no. (%) | 1.000 | 1.000 | ||||
Mutation | 5 (11.1) | 5 (11.1) | 2 (5.6) | 2 (5.6) | ||
Wild type | 40 (88.9) | 40 (88.9) | 34 (94.4) | 34 (94.4) | ||
CEBPA/no. (%) | 1.000 | 1.000 | ||||
Mutation | 2 (4.4) | 1 (2.2) | 4 (11.1) | 4 (11.1) | ||
Wild type | 43 (95.6) | 44 (97.8) | 32 (89.9) | 32 (88.9) | ||
IDH1/no. (%) | 0.012012 | 0.514 | ||||
Mutation | 0 (0.0) | 7 (15.6) | 4 (11.1) | 7 (19.4) | ||
Wild type | 45 (100.0) | 38 (84.4) | 32 (88.9) | 29 (80.6) | ||
IDH2/no. (%) | 1.000 | 0.710 | ||||
Mutation | 4 (8.9) | 5 (11.1) | 3 (8.3) | 5 (13.9) | ||
Wild type | 41 (91.1) | 40 (88.9) | 33 (91.7) | 31 (86.1) |
Prognostic value of miR-425 in patients with chemotherapy and allo-HSCT treatment
MiR-425 was independently associated with a clinical outcome in AML
Variables | EFS | OS | ||
---|---|---|---|---|
HR (95% CI) | P-value | HR (95% CI) | P-value | |
Univariate analyses | ||||
MiR-425 (high vs. low) | 0.449 (0.279–0.721) | 0.001 | 0.506 (0.316–0.811) | 0.005 |
WBC (≥ 20 vs. < 20 × 109/L) | 0.939 (0.594–1.484) | 0.786 | 0.936 (0.591–1.484) | 0.779 |
FLT3-ITD (positive vs. negative) | 1.242 (0.693–2.224) | 0.467 | 1.192 (0.665–2.136) | 0.555 |
NPM1 (mutated vs. wild) | 1.168 (0.721–1.893) | 0.527 | 1.044 (0.640–1.704) | 0.862 |
DNMT3A (mutated vs. wild) | 1.491 (0.909–2.446) | 0.114 | 1.432 (0.868–2.362) | 0.160 |
RUNX1 (mutated vs. wild) | 1.464 (0.700–3.064) | 0.312 | 1.591 (0.759–3.335) | 0.219 |
TP53 (mutated vs. wild) | 2.949 (1.510–7.561) | 0.002 | 2.898 (1.487–5.694) | 0.002 |
CEBPA (mutated vs. wild) | 2.963 (0.910–9.648) | 0.071 | 2.901 (0.892–9.434) | 0.077 |
IDHI/IDH2 (mutated vs. wild) | 1.006 (0.570–1.775) | 0.983 | 0.954 (0.532–1.710) | 0.874 |
NRAS/KRAS (mutated vs. wild) | 1.143 (0.601–2.172) | 0.684 | 1.188 (0.625–2.260) | 0.599 |
MLL-PTD (mutated vs. wild) | 0.836 (0.305–2.291) | 0.727 | 0.910 (0.332–2.495) | 0.855 |
Multivariate analyses | ||||
MiR-425 (high vs. low) | 0.432 (0.266–0.703) | 0.001 | 0.502 (0.311–0.811) | 0.005 |
FLT3-ITD (positive vs. negative) | 1.582 (0.868–2.883) | 0.134 | – | – |
TP53 (mutated vs. wild) | 2.737 (1.377–5.438) | 0.004 | 2.519 (1.286–4.933) | 0.007 |
CEBPA (mutated vs. wild) | 3.746 (1.102–12.736) | 0.034 | 3.228 (0.959–10.864) | 0.058 |
Variables | EFS | OS | ||
---|---|---|---|---|
HR (95% CI) | P-value | HR (95% CI) | P-value | |
Univariate analyses | ||||
MiR-425 (high vs. low) | 1.037 (0.624–1.724) | 0.888 | 1.073 (0.626–1.840) | 0.798 |
WBC (≥ 20 vs. < 20 × 109/L) | 1.530 (0.910–2.571) | 0.108 | 0.949 (0.554–1.628) | 0.851 |
FLT3-ITD (positive vs. negative) | 1.873 (1.020–3.437) | 0.043 | 1.998 (1.053–3.788) | 0.034 |
NPM1 (mutated vs. wild) | 0.913 (0.515–1.619) | 0.755 | 0.879 (0.478–1.671) | 0.678 |
DNMT3A (mutated vs. wild) | 1.106 (0.615–1.989) | 0.737 | 1.269 (0.686–2.347) | 0.447 |
RUNX1 (mutated vs. wild) | 1.375 (0.650–2.907) | 0.404 | 2.253 (1.046–4.849) | 0.038 |
TP53 (mutated vs. wild) | 1.579 (0.565–4.411) | 0.383 | 3.788 (1.289–11.133) | 0.015 |
CEBPA (mutated vs. wild) | 0.853 (0.366–1.989) | 0.713 | 0.644 (0.256–1.620) | 0.350 |
IDHI/IDH2 (mutated vs. wild) | 0.761 (0.417–1.389) | 0.374 | 0.802 (0.422–1.524) | 0.500 |
NRAS/KRA S (mutated vs. wild) | 1.373 (0.622–3.034) | 0.433 | 0.658 (0.261–1.657) | 0.374 |
MLL-PTD (mutated vs. wild) | 6.093 (2.051–18.098) | 0.001 | 3.106 (1.104–8.741) | 0.032 |
Multivariate analyses | ||||
WBC (≥ 20 vs. < 20 × 109/L) | 1.691 (0.973–2.940) | 0.062 | – | – |
FLT3-ITD (positive vs. negative) | 1.740 (0.934–3.239) | 0.081 | 2.549 (1.306–4.975) | 0.006 |
TP53 (mutated vs. wild) | 2.657 (0.877–8.048) | 0.084 | 5.841 (1.895–18.009) | 0.002 |
RUNX1 (mutated vs. wild) | – | – | 3.007 (1.355–6.673) | 0.007 |
MLL-PTD (mutated vs. wild) | 6.028 (2.001–18.158) | 0.001 | – | – |
Patients with low expression of miR-425 benefited from allo-HSCT treatment
Biologic Insights
GO ID | GO terms | Percentage of Members of the GO Term Present in the miR-425 Profile | P-value |
---|---|---|---|
GO:0008152 | Metabolic process | 62.8 | 0.004 |
GO:0044237 | Cellular metabolic process | 59.6 | 0.002 |
GO:0043170 | Macromolecule metabolic process | 55.7 | < 0.001 |
GO:0044267 | Cellular protein metabolic process | 30.7 | 0.029 |
GO:0031326 | Regulation of cellular biosynthetic process | 29.4 | 0.006 |
GO:0009889 | Regulation of biosynthetic process | 29.4 | 0.008 |
GO:0010468 | Regulation of gene expression | 29.4 | 0.009 |
GO:0051252 | Regulation of RNA metabolic process | 25.0 | 0.026 |
GO:0065009 | Regulation of molecular function | 20.5 | 0.019 |
GO:0006468 | Protein phosphorylation | 15.3 | 0.011 |
GO:0009790 | Embryo development | 8.9 | 0.026 |
GO:0051301 | Cell division | 7.7 | 0.004 |
GO:0032101 | Regulation of response to external stimulus | 7.7 | 0.019 |
GO:0010608 | Posttranscriptional regulation of gene expression | 5.8 | 0.025 |
GO:0042787 | Protein ubiquitination | 3.8 | 0.026 |