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A.L. Fedullo et al.
defined ΔMEF2C-long. The other category, detected in seven patients, was smaller (5.4 Kb) and involved only exon 2, and was called ΔMEF2C-short (Figure 2A). ddPCR confirmed MEF2C lesions in all cases. No MEF2C muta- tions were identified.
overall survival (62.6% versus 40.2%; P=0.02) (Figure 3D). The presence of ΔMEF2C-long was associated with a higher rate of CMR achievement (P=0.05); this effect was not influenced by the protocol or the tyrosine kinase inhibitor used (imatinib or dasatinib). Furthermore, ΔMEF2C-long cases were also associated with a signifi-
Table 2. Minimal common region (MCR) of identified focal lesions.
KRAS deletions (ΔKRAS) were detected in seven cases (6%); the focal lesion of KRAS started in the 5’ untranslat- ed region and ended in intron 1-2, involving the first non- codifying exon (Figure 2B). The minimal common region consisted of 135 Kb. KRAS was not affected by mutations.
Deleted gene
FOCAD
CDK6 PTPRD MEF2C BTLA
JAK2 ADD3 SLX4IP CD200 HBS1L ATP10A TOX
KRAS ARHGAP24 EBF1
LEF1 MDM2 TCF12 ERG
N. of patients (%)
29 (25)
24 (20.7) 21 (18.1) 21 (18.1) 21 (18.1) 20 (17.2) 18 (15.5) 17 (14.6) 17 (14.6) 16 (13.7) 14 (12) 8 (6.9)
7 (6)
7 (6) 6 (5.1) 5 (4.3) 5 (4.3) 4 (3.4) 2 (1.7)
MCR (hg19)
chr9: 20685149 - 20759956
chr7: 92456635 - 92266647 chr9: 8153932 - 8854489 chr5:88122179 - 88127630 chr3:112154702 - 112217769 chr9: 5123013 - 5234403 chr10: 111795029 - 111853667 chr20: 10417444 - 10451891 chr3:112054292 - 112217769 chr6: 135375338 - 135418257 chr15: 26055568 - 26103185 chr8:60028851 - 60110235 chr12: 25402194 - 25537468 chr4:86493655 - 86436188 chr5: 158440156 - 158164599 chr4:109034392 - 109084557 chr12:69159076 - 69205287 chr15:57294905 - 57399047 chr21:39772775 - 39788683
Impact of known and novel deletions on complete molecular response achievement and disease-free survival
We did not find significant differences between patients with ΔIKZF1 and IKZF1 wild-type cases with regard to achievement of complete molecular response (CMR) or disease-free survival (DFS) (Online Supplementary Figure S2). Further stratification according to IKZF1 isoforms showed that patients with the dominant-negative isoform had a lower DFS rate (23.3%; P=0.039) compared to patients with the other isorforms, particularly wild-type (53.3%; P=0.016) and haploinsufficient cases (40.3%; P=0.015); the DFS rate of the miscellaneous group (34.1%) did not differ significantly from that of the dominant-neg- ative cases (Figure 3A). These differences were not statis- tically significant in the overall survival analysis (Figure 3B).
We also investigated the outcome of ΔIKZF1+CDKN2A and/or PAX5 cases. The CMR rate did not differ between ΔIKZF1+CDKN2A and/or PAX5 and ΔIKZF1-only cases; contrariwise, ΔIKZF1+CDKN2A and/or PAX5 patients had a significantly worse DFS than ΔIKZF1-only cases (43.3% versus 24.9%; P=0.026) (Figure 3C) and an inferior
A
BC
D
Figure 1. Overall load and incidence of genetic lesions in Philadelphia chromosome-positive acute lymphoblastic leukemia. (A) Distribution of copy number aber- rations in the whole cohort and across different protocols. (B) Percentages of gross chromosomal aberrations. (C) Percentages of deletions of known genes in the whole cohort (n=116) and in the different studies analyzed. (D) Heatmap of IKZF1, CDKN2A/B, and PAX5 deletions in the whole cohort.
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