Page 98 - Haematologica-April 2018

P.B. Sinclair et al.
Table 3. The expression of genes in xenograft-derived iAMP21-ALL cells within and neighboring regions of bi-allelic deletion of chromosomes 10
and 9.
Chromosome 10
Gene Genomic position RCM
ZNF518A 96,129,715-96,205,288 3513 BLNK 96,191,702-96,271,587 18573 DNTT 96,304,396-96,338,564 166450 OPALIN 96,343,216-96,359,365 458 TLL2 96,364,606-96,513,918 235 TM9SF3 96,518,109-96,587,452 14506 PIK3AP1 96,593,312-96,720,514 35985 LCOR 96,832,260-96,981,043 8942 SLIT1 96,998,038-97,185,920 0 ARHGAP19 97,222,173-97,292,673 2486
3°1e
1°4b
Xenograft
RCM CN RCM
2474 2 3316
2°2e 2°3d
CN RCM
2 2746
2
2
2
2
2
2
2
2 0 2 4151
918
1411
CN
1
CN
2
2
2
2 2 2 2 2 2 2
2
2 2 2 2 2 2 2 2
0 11315 2 6251
2
1 8325
Chromosome 9
21,802,543-21,937,651
CDKN2A
CDKN2B
CDKN2B-AS1 21,994,778-22,121,097 DMRTA1 22,446,841-22,455,740 ELAVL2 23,690,104-23,826,337 TUSC1 25,676,389-25,678,440 CAAP1 26,840,685-26,892,804 PLAA 26,904,083-26,947,463
1
1 1
1 1
1
1
170269 2 215495
698 2 471
152 2 111 12641 2 19522 20616 2 28820 7568 2 4218 0 2 0 3164 2 3524
2 0 1846
883 62 82
1 0 1 0 1 415 1 1307
1230 1 1939
MTAP
10
00
21,967,753-21,995,301 22,002,903-22,009,363
0000 0000 0
00
00 00
0 0
0 1
0 0
00 00
0
0 686
1 1 1
0
0 576
00
10
642
Gene expression units are read counts / million (RCM). Regions of complete / near complete loss of expression and copy number (CN) of 0 are highlighted.
ing occurred in areas of normal bone marrow before malig- nant cell infiltration suggesting systemic suppression of normal hematopoiesis, possibly through a mechanism such as cytokine scavenging, as recently reported to account for cytopenia in acute myeloid leukemia.26 The effect did not correlate with late stage disease, as the mean times between transplantation and culling were almost identical and spleen weights were greater and CNS infiltra- tion heavier for mice with no evidence of niche destruc- tion. Further analysis demonstrated that niche destruction is not restricted to the iAMP21-ALL subtype but is proba- bly less common than suggested by our initial data.
Global analysis of genomes from the iAMP21-ALL patients and xenografts revealed a dynamic branching of genomic architecture, similar to that reported previously for B-ALL.4,6,7,27,28 However the rate of newly emergent CNA and their diversity in iAMP21-ALL xenografts suggested a leukemia-initiating cell compartment characterized by greater genetic heterogeneity compared with other B-ALL sub-types. Genomic arrays revealed an average of five CNA per transplanted iAMP21-ALL sample, while similar analysis defined only a single change among seven KMT2A-rearranged infant ALL samples engrafted into multiple mice.28 Additionally, among 12 BCR-ABL1-posi- tive ALL samples, half showed no CNA discordance in xenografts.27 The iAMP21-ALL primografts also developed disease with a relatively long latency. Together with the older age of patients at diagnosis of iAMP21-ALL,12 these data suggest that the primary iAMP21 rearrangement con- fers only a moderate growth advantage, producing an
indolent disease course over which diverse genetic sub- clones are sampled. As genetic diversity has been linked to clinical aggressiveness,29 this clonal heterogeneity of iAMP21-ALL may underlie the affected patients’ poor response to standard therapy.17
Although each iAMP21 chromosome is unique with respect to the balance of regions amplified and deleted, within clinical trials patients are treated homogeneously.17 Our data support this approach, as they further confirm iAMP21 to be a primary abnormality, because the region identified as consistently amplified and spared from chro- mothripsis,11 was always retained. However in xenografts from one patient, we observed segregation of a structurally evolved iAMP21 chromosome which, together with other CNA, marked a clone that appeared to confer an excep- tionally strong growth advantage. Structural evolution of iAMP21 has not been reported previously, although only few presentation/relapse pairs have been analyzed at the whole genome level and FISH is usually targeted only to the RUNX1 gene. This case demonstrates that even after stabilization of the iAMP21 chromosome evident at the time of diagnosis, these rearrangements can undergo fur- ther evolution, potentially influencing clinical features and treatment response. However this iAMP21 chromosome may be atypical, as it was reported to be a ring chromo- some, which are known to be inherently unstable struc- tures.30 It may be that other iAMP21 ring chromosomes have a tendency to further evolution, but this case was the only one included in this study. Whether this iAMP21 chromosomal evolution acted as a driver of leukemia pro-
21
344
1 40 21 0
haematologica | 2018; 103(4)