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RAS pathway alterations in pediatric AML
Table 2. Summary of characteristics of pediatric acute myleoid leukemia patients with PTPN11 and CBL mutations.
Gene UPN Nucleotide change*
Amino acid Sex Age, WBC,
Cytogenetics
45,XY,-7[1]/45,sl,t(3;12) (q26;p13)[18]/46,XY[1] 46,XX[20] 46,XX,add(12)(p11)[12]/46,XX[8}
47,XX,t(7;12)(q36;p13),+19[20] N/A
46,XX[20]
Additional CR Relapse Event SCT Prognosis genetic
PTPN11 45 52
113
127 142 156
177 249 300 367 375
415
417
425 438
change*
E76V M
V45L F A72V F
T73I F G503A M A72D F A227G E76G M
G179T G60V F
C1478T T493I M
G226A E76K M
G181T D61Y M G1508C G503A F
G1508C G503A M
G205A E69K M A227T E76V F
y ×109/L
4.8 33.9
aberrations
-
WT1, KMT2A-PTD
CBL, KRAS, KMT2A-ELL, WT1, STAG2
RAD21 KMT2A-MLLT3 FLT3-ITD, NPM1
A227T
G133C C215T
- +
- - + +
+ + + + + -
C218T G1508C C215A
14.1 10.3
0.4 6.9 11.5 2.9
11.8
16.5 17.8
17.1 190.5 4.5 25.2
60.1
Death
Death Alive
Alive Death Alive Death
delins LSSLSLSQV
p.M469V M
47,XY,+8[20] - 11.6 38.2 47,XX,+18[1]/46,XX[19] NPM1
+ - + +
Death Death
45,XY,-7[1]/45,sl,t(11;21) - - - (q13;q22)[19]
46,XX[20] NRAS, KMT2A-PTD, + RUNX1
+ +
Alive
4.2 4.6 46,XY,t(8;21)(q22;q22)[2]/46,sl, - + del(9)(q?)[7]/46,XY[11]
7 9.9 47,XY,+11[18]/54,idem,+X, NF1 + +10,+11,+13,+14,+20,+21[1]/46,XY[1]
1.9 16.1 46,XY,-7,+mar[17]/46,idem,del(6)(q?)[3] RUNX1 - 12.3 1.9 45,XX,ins(1;?)(q21;?),add(4)(q12) NF1 +
+ +
+ - + +
+ + + + - + + +
+
- - - Alive - - - Alive
CBL 2 c.1174_1181delins p.392-394 M
5.6 51.7
9.8 73.2 13.6 161.0
2.3 172.0 7.4 168.1
add(7)(q36),der(17;18)(q10;q10)[20] 46,XY,t(11;19)(q23;p13.1)[17]/ KMT2A-ELL, +
47,idem,+8[1]/46,XY[2] STAG2
46,XY[20] NPM1 + 49,XX,+8,+10,+12[20] FUS-ERG +
46,XY,t(9;11)(p22;q23)[16]/46,XY[4] KMT2A-MLLT3 -
Alive Death
Alive
Alive Death
Death
TTATCATCCTTATCAT TATCACAGGT
67 c.A1405G
97 c.T1248G p.C416W F
167 c.1096-75_1218 p.366_406del M delinsAAAGGCT
184 c.1183_1227+27del p.395_409del M 262 c.1096-40_1227+35del p.366_409del M
9.9 20.5 46,XY,t(8;21)(q22;q22)[17]/ KIT 45,X,-Y,t(8;21)(q22;q22)[3]
15.1
12.3
54.2 159.3
47,XY,inv(16)(p13.1q22),+22[20] - 46,XY,inv(16)(p13q22)[20] NRAS, NF1
- + +
+ + +
+ + +
- - -
+ + +
+ + +
- +
+ +
+ - - - Alive
+ - - - Alive
+ - - - Alive
UPN: unique patient number; WBC: white blood cell count; CR: complete remission; SCT: stem cell transplantation; N/A: not applicable; M: male; F: female.; y: years. *NCBI reference sequence; PTPN11, NM_002834; CBL, NM_005188.
studies have found inconsistent evidence of the clinical sig- nificance of NRAS mutations.8,9 In the present study, NRAS mutations were associated with favorable prognosis. This seemed attributable to the characteristics of patients with NRAS mutations, i.e., high frequency of CBFB-MYH11 with no other poor prognostic factors.
11q-UPD was detected in only one patient with a CBL missense mutation, which might be consistent with a previous study reporting that somatically acquired CBL deletions are frequently heterozygous, whereas most missense mutations are homozygous as a consequence of 11q-UPD.50 We summarized previous reports on CBL mutations in AML in the Online Supplementary Table S6. CBL mutations were previously shown to be associated with CBF-AML.13 In the present study, three of six patients with CBL mutations had CBF-AML; however, there was no significant association in this respect (Figure 1, Table 2). Owing to the low incidence of CBL mutation, its prognostic significance is not well characterized.10,12,13 Although we did not observe any significant prognostic
impact of CBL mutations in our cohort, all three patients without CBF experienced relapse and died (Table 2). These results might suggest that non-CBF patients with CBL mutation show poor prognosis.
RAS pathway alterations are also a major cause of JMML; in addition, each of these alterations are of prog- nostic relevance in patients with JMML.51,52 In previous studies, JMML patients with PTPN11 and NF1 mutations showed significantly poor prognosis.51,52 On the other hand, JMML patients with NRAS mutations exhibited favorable outcomes.51,52 In our study, the prognostic impact of NF1, PTPN11, and NRAS was similar to that observed in JMML. However, we are unable to explain this similarity because the transformation of JMML to AML is rare.53
There may be some possible limitations in this study. First, we analyzed PTPN11, CBL, NRAS and KRAS muta- tions by Sanger sequencing because the mutation hotspots of these genes were well known. Although the frequency of these mutations was similar to the previous reports by
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