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K. Van Roosbroeck et al.
tially expressed human miRNA are located in regions genetically altered in RS, we first analyzed the eight genomic loci of the enlarged signature-related miRNA in 15 paired CLL/RS cases for which samples at CLL diagno- sis and at RS diagnosis were available.17 We found that, in RS samples, three cases (20%) had a gain of the miR- 181a/b clusters on either chromosome 1q32 or 9q33, three cases (20%) had a loss of miR-26a-1 and a-2 loci on either chromosome 3p22 or 12q14, two cases (13.5%) had a gain of miR-21 locus at 17q23, and one case (6.67%) had a loss of miR-150 locus at 19q13 (Figure 4A). We then considered a larger series of cases of RS (n=59) and CLL phases (n=28). In accordance with the above- presented expression data, we observed a similar pattern of miRNA-specific genetic aberrations: RS patients more frequently presented gains affecting miR-21, miR-146a and miR-181a/b genomic loci (Online Supplementary Figure S4A). Finally, we took advantage of a series of 737 genomic profiles obtained in mature lymphoid tumors to compare the frequency of DNA copy number aberrations with that observed in RS.17,26-29 The same miRNA loci
were sites of gains (miR-181a/b, 6% and 8% at 1q or 9q, respectively; miR-21, 4%; miR-146a, 3%; miR-146b, 0.2%) or losses (miR-150, 6%; miR-26a, 3% and 0.1% at 3p or 12q, respectively) in mature lymphoid tumors (Figure 4B and Online Supplementary Figure S4B), but at a significantly lower frequency than that observed in RS samples (P=0.017 and c2=5.669, see Online Supplementary Figure S4C). Altogether, these data suggest that, at least in some cases, Richter-related miRNA are deregulated due to DNA copy number changes, which occur during the transformation process, and are enriched with respect to non-Richter B-cell malignancies. The mechanism(s) for the miRNA expression deregulation for the majority of Richter cases has still to be identified.
The microRNA network is reprogrammed during Richter transformation
Although it is known that changes in miRNA expres- sion are involved in the initiation and development of CLL,30 we further investigated whether analysis of the miRNA interactor network could add more information
Table 1. Characteristics of patients with Richter syndrome and chronic lymphocytic leukemia in the cohort from the University of Texas MD Anderson Cancer Center.
Characteristic
Age at diagnosis, years Median
Range
Sex Male Female
Rai stage 0
1 2 3 4 NA
FISH
del13q
NL cyto/FISH trisomy 12 del11q del17p
NA
ZAP70 Positive Negative NA
CD38
Positive (>=20%) Negative (<20%) NA
B2 microglobulin level Median
Range
Richter (n=27) CLL (n=23) N. % N. %
P-value
0.1973
>0.9999
0.0947
0.0328
0.0239
<0.0001
0.5718
0.0051
continued from the previous coloum
Characteristic
IGHV
Richter (n=27) CLL (n=23) N. % N. %
P-value
0.1459
<0.0001
0.3821
0.0007 0.0079
0.0083
0.0083
54 31-78
17
10
4 11 5 4 1 2
8 4 8 6 5 4
6 0 21
17 3 7
59 43-70
63.0 14
18 66.7 7 30.45 5 18.5 7 30.45
60.9
Unmutated
Mutated
NA 4 14.8 9 39.1
37.0 9 39.1
Time to transformation (months)
14.8 7
40.7 13 56.5 18.5 1 4.3 14.8 0 0.0
3.7 2 8.7
Median
Range
Survival
Dead
Alive at last follow-up
Survival time (months) Median
Range
LDH at diagnosis Normal (≤18 UI/L) Elevated (>618 UI/L) NA
Median Range
69 NA
8-213 NA
22 81.5 1 4.35 5 18.5 22 95.7
108 96
20-245 15-234
12 44.4 21 91.3 15 55.6 2 8.7 0 0.0 0 0.0
647 513 303-1587 357-1175
30.5
7.4 0
29.6 16 14.8 0 29.6 5 22.2 3 18.5 1 14.8 2
22.2 8 0.0 10 77.8 5
63.0 4 11.1 15 25.9 4
0.0
69.6 0.0 21.8 13.1 4.35 8.7
34.8 43.5 21.8
17.4 65.3 17.4
Time to first treatment (months)
Median 10 39 Range 0-156 0-156
Number of treatments (including SCT)
0 1 3.7 4 17.4 1 6 22.2 13 56.55 2 5 18.5 1 4.35 3 2 7.4 1 4.35 4 6 22.2 1 4.35 5 4 14.8 0 0.0 6 3 11.1 0 0.0 NA 0 0 3 13.1
B microglobulin 2
Positive (≥2 mg/mL) Negative (<2 mg/mL) NA
25 1
92.6 18
3.7 2 8.7
78.3 1 3.7 3 13
3.6
1.6-10
2.4
NA: not available; FISH: fluorescence in situ hybridization; LDH: lactate dehydrogenase; SCT: stem cell transplantation.
1-4.1
continued in the next coloum
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haematologica | 2019; 104(5)