SUPPLEMENTAL DATA
Supplemental Figure 1. Highly variable expression of MMRN1 in pediatric AML patient specimens. Initial discovery studies using microarray data from a set of 211 diagnostic specimens from participants of COG trials (including 58 from AAML03P1 [52 of which were also available for qRT-PCR analyses] and 130 from AAML0531 [122 of which were also available for qRT-PCR analyses]) and 4 normal bone marrow (NBM) specimens. The MLL subset of AMLs was used to arbitrarily define a cut-off of >9.0 (indicated with dashed line) for “high” (n=35, top 16.6%) and ≤9.0 for “low” (n=176, bottom 83.4%) MMRN1 expression, respectively.
Supplemental Figure 2. Clinical outcome in patients with high and low MMRN1 expression. Estimates of the probability of (A) OS and (B) EFS in patients with high (n=35) vs. low (n=176) MMRN1 expression.
Supplemental Figure 3. Relationship between bone marrow blast percentage and MMRN1 expression in the AAML0531 patient cohort. Spearman correlation: p=0.731.
SUPPLEMENTAL TABLE 1. Comparison of Baseline Characteristics of Patients with Low (<0.5) vs. High (≥0.5) MMRN1 Expression in AAML03P1
Patient Characteristics
Relative MMRN1 Expression
P-value
Low (<0.5)
n = 138
High (≥0.5)
n = 45
Median Age, years (range)
10.9 (0.1-20.8)
6.1 (0.2-18.0)
0.020
Male Sex, n (%)
86 (62%)
24 (53%)
0.285
WBC (x103/µL) - median (range)
37.8 (1.8 - 495)
23.7 (2.1 - 409)
0.827
Median bone marrow blasts, %
71 (5-100)
72 (2-100)
0.572
Platelet count (x103/µL) - median (range)
45.5 (4 - 578)
64 (10 - 520)
0.028
Hemoglobin (g/dL) - median (range)
8.6 (3.3 - 15.6)
8.3 (4.3 - 14.0)
0.717
Cytogenetics, n (%)
Normal
30 (24%)
6 (14%)
0.151
t(8;21)(q22;q22)
22 (18%)
0 (0%)
0.003
inv(16)/t(16;16)(p13.1;q22)
24 (20%)
4 (9%)
0.124
t(9;11)(p22;q23) or other abn 11q23
19 (15%)
12 (28%)
0.071
t(6;9)(p23;q34)
5 (4%)
1 (2%)
1.000
Monosomy 7
0 (0%)
5 (12%)
<0.001
Del7q
2 (2%)
2 (5%)
0.276
-5/5q-
0 (0%)
2 (5%)
0.066
Trisomy 8
9 (7%)
4 (9%)
0.743
Other
12 (10%)
7 (16%)
0.270
Unknown
15
2
Risk Group, n (%)
Standard
46 (36%)
30 (70%)
<0.001
Low
66 (52%)
4 (9%)
<0.001
High
15 (12%)
9 (21%)
0.138
Unknown
11
2
Molecular alterations, %
FLT3/ITD
15%
5%
0.075
NPM1 mutation
10%
0%
0.040
CEBPA mutation
9%
0%
0.040
WT1 mutation
14%
7%
0.249
Hepatomegaly, n (%)
26%
38%
0.149
Splenomegaly, n (%)
32%
32%
0.971
Extramedullary disease, n (%)
13%
7%
0.244
CNS disease, n (%)
7%
0%
0.063
Chloroma, n (%)
7%
7%
1.000
SUPPLEMENTAL TABLE 2. Univariate and Multivariate Regression Models of OS, EFS, and RR for the AAML0531 Study, with Outcome Censored at Time of HCT
OS
EFS
RR
n
HR
95% CI
P-value
n
HR
95% CI
P-value
n
HR
95% CI
P-value
Univariate Model
MMRN1 Expression
<0.5
590
1 (Ref)
590
1 (Ref)
449
1 (Ref)
≥0.5
160
2.197
1.65-2.93
<0.001
160
1.864
1.46-2.38
<0.001
106
2.088
1.52-2.87
<0.001
Disease Risk*
Standard-risk
349
1 (Ref)
349
1 (Ref)
251
1 (Ref)
Low-risk
283
0.326
0.23-0.46
<0.001
283
0.428
0.33-0.55
<0.001
233
0.389
0.28-0.53
<0.001
High-Risk
98
1.334
0.91-1.95
0.137
98
1.694
1.23-2.33
0.001
56
1.262
0.75-2.11
0.379
BM Blast % (per 20%)
697
1.108
0.98-1.25
0.097
697
1.244
1.13-1.38
<0.001
519
1.262
1.10-1.44
0.001
Platelet Count (per 50x103/µL)
748
1.052
0.99-1.11
0.083
748
1.035
0.99-1.09
0.164
553
1.038
0.97-1.11
0.262
Multivariate Model**
MMRN1 Expression
<0.5
538
1 (Ref)
538
1 (Ref)
415
1 (Ref)
≥0.5
144
1.554
1.12-2.15
0.008
144
1.353
1.03-1.78
0.031
93
1.442
1.01-2.06
0.044
Disease Risk*
Standard-risk
323
1 (Ref)
323
1 (Ref)
232
1 (Ref)
Low-risk
267
0.282
0.19-0.42
<0.001
267
0.411
0.30-0.56
<0.001
223
0.428
0.29-0.63
<0.001
High-Risk
92
1.033
0.68-1.56
0.875
92
1.412
1.00-1.99
0.048
53
1.073
0.62-1.87
0.802
BM Blast % (per 20%)
682
0.984
0.87-1.11
0.793
682
1.152
1.04-1.28
0.007
508
1.208
1.05-1.38
0.006
*See methods section for definition of cytogenetic/molecular disease risk **Models were also adjusted for treatment arm and age.
SUPPLEMENTAL TABLE 3. Relative MMRN1 expression in paired samples of CD34+/CD33- and CD34+/CD33+ cells
Cell Population
AML Specimen
#1
#2
#3
#4
#5
#6
#7
#8
#9
#10
MMRN1/GUSB Expression
CD34+/CD33-
1.79
0.03
0.09
4.82
0.01
1.64
0.33
1.35
0.06
0.32
CD34+/CD33+
1.14
0.07
0.06
1.44
0.02
0.48
0.13
0.73
0.11
0.15
FACS was used to separate less mature CD34+/CD33- and more mature CD34+/CD33+ cells. Equal amounts of total RNA were then used to quantify MMRN1 and GUSB transcript levels by qRT-PCR.
MM
RN
1 ex
pres
sion
(log
bas
e 2)
11.2 10.4
9.7 8.9 8.1 7.4 6.6 5.8 5.0 4.3 3.5
M
M
R
N
1
e
x
p
r
e
s
s
i
o
n
(
l
o
g
b
a
s
e
2
)
11.2
10.4
9.7
8.9
8.1
7.4
6.6
5.8
5.0
4.3
3.5
0 2 4 6 8 100
25
50
75
100
Years from Study Entry
Ove
rall
Surv
ival
P=0.0040
0 2 4 6 8 100
25
50
75
100
Years from Study Entry
Even
t-fre
e Su
rviv
al
MMRN1 LowMMRN1 High
P=0.0049
A B
0246810
0
25
50
75
100
Years from Study Entry
O
v
e
r
a
l
l
S
u
r
v
i
v
a
l
P=0.0040
0246810
0
25
50
75
100
Years from Study Entry
E
v
e
n
t
-
f
r
e
e
S
u
r
v
i
v
a
l
MMRN1 Low
MMRN1 High
P=0.0049
A
B
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