DNA Copy Number Alterations and Copy Neutral Loss of Heterozygosity in Adult Ph-Negative Acute B-Lymphoblastic Leukemia: Focus on the Genes Involved
Abstract
:1. Introduction
2. Results
2.1. Clonal Heterogeneity in B-ALL
2.2. Molecular Karyotype of B-ALL
2.3. Molecular Karyotype Is Not Associated with MRD
2.4. Loss of Both Alleles—Biallelic or Homozygous Deletion
2.5. HLA-haplotype Loss
2.6. Loss of 3p21.3 Tumor Suppressor Genes Cluster
2.7. Copy Number Alterations and cnLOH in Genes Involved in the Pathogenesis of B-ALL
2.8. The Prognostic Significance of Various Genetic Abnormalities
3. Discussion
4. Materials and Methods
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Parameter | B-ALL (n = 36) |
---|---|
Male:Female | 21:15 |
Age, median | 34.1 (19–53) years |
Leukocytes, 10 × 9/L | 7.66 (1.09–466.53) |
LDH | 624 (148–7348.8) |
Blast cells in peripheral blood, % | 40 (0–95) |
Blast cells in the bone marrow, % | 88.8 (29–98) |
Immunophenotype, EGIL, WHO | B-I 5 (13.8%) |
B-II 30 (83.3%) | |
B-III 1 (2.7%) | |
B-IV 0 (0%) | |
Standard cytogenetics | 36 |
+ mitosis | 35 (97.2%) |
− mitosis | 1 (2.8%) |
Karyotype | 35 |
Normal | 7 (20.0%) |
Abnormal: | 28 (80.0%) |
CNS leukemia | 3 (8.3%) |
Extramedullary disease | 14 (38.8%) |
MRD-status (+70 day) | 34 |
MRD+ | 18 |
MRD- | 16 |
CR: | |
After 2nd induction (+70 day) | 16 |
Refractory disease | 1 |
Early Death | 1 |
N° | Sex | Age | Diagnosis | CCA Data [mitoses count] | CMA Data | FISH |
---|---|---|---|---|---|---|
1 | f | 31 | B-II | no mitosis | (X,1-22)×2 | n/rvl t(9;22)(q34;q11); t(11q23)/MLL |
2 | f | 26 | B-II | 46,XX,t(4;11)(q21;q23)[7]/46,XX [13] | (X,1-22)×2 | 21% t(11q23)/MLL |
n/rvl t(9;22)(q34;q11) | ||||||
3 | f | 54 | B-II | 50,XX,+X,+8,+9,i(9)(q10),+22[10]/46,XX [4] | (X)×3, 2p16.3×1, 5q35.2q35.3×2 hmz, 7p12.3p12.1×1, (8)×3, 9p24.3p21.3×2 hmz, 9p21.3×0, 9p21.3p13.1×2 hmz, (9q)×4, 17q11.2q11.2×2 hmz, (22) ×3 | 94%++ABL/9q34 ++BCR/22q11 |
n/rvlt(9;22)(q34;q11); t(11q23)/MLL | ||||||
4 | f | 34 | B-I | 47,XX,+X,t(4;11)(q21;q23)[17]/46,XX [3] | (X)x3[0.6],1p21.2p21.1x2 hmz,3q25.31q26.1x2 hmz, 3p21.1p14.2×2 hmz,3p22.1p21.31×2 hmz, 4q34.3q34.3×2 hmz,5p13.1q11.2×2 hmz, 6p22.3p22.3×2 hmz,8p23.1p22)×2 hmz, 9q22.31q31.1×2 hmz,10q25.3q26.13×2 hmz, 10q25.1q25.2×2 hmz,11q22.3q23.2×2 hmz | 90% t(11q23)/MLL |
n/rvl t(9;22)(q34;q11) | ||||||
5 | f | 34 | B-II | 46,XX [20] | (X)×1 [0.2], 2q24.1q24.1×2 hmz, (3)×1 [0.19], 4q31.3q32.1×1 [0.2], (7)×1 [0.19],7q31.2q31.31×2 hmz, (8)×3 [0.31], (9)×1 [0.19], (10)×3 [0.29], | 12% + MLL/11q23, +BCR/22q11 |
(14)×3 [0.3], (15)×1 [0.2],(16)x1 [0.19],(20)×1 [0.17],(21)x3 [0.31] | n/rvl t(9;22)(q34;q11); t(11q23)/MLL | |||||
6 | m | 32 | B-II | 46,XY,der(6),-11,+mar or der(11?)[6]/46,XY [14] | 3p21.31×1,6q16.1q22.1×1, 9p24.3×3,11p14.3p12×1, 11p11.2q12.1×1,11q14.2q14.3x1, 11q22.1q23.3×1,11q23.3q24.1×1, 11q24.1×1,12p13.31×3, 19p13.3×1 | n/rvl t(9;22)(q34;q11); t(11q23)/MLL |
7 | f | 24 | B-II | 81-85,XX, ?-X, del (6)(q22)*2, add(11)(q2?5),+3-4 mar, inc [cp2]/ | Xp22.33p11.3×1 [0.2],Xp11.3q28×1 [0.5], 3p26.3p12.2×1 [0.3], 3p12.1p11.1×2 hmz, | n/rvl t(9;22)(q34;q11); t(11q23)/MLL |
46,XX [18] | 3q25.33q29×3 [0.3], 6q16.3q24.3×1 [0.6], (9)×1 [0.21], (11)×1 [0.3], 12p13.33p13.2×1 [0.22], 12p13.2p12.1×2 hmz [0.5], 12p11.23q22×3 [0.3], 12q22q24.33×1 [0.2], (15)×1 [0.72], 17p13.3q21.31×1 [0.2], 17q21.31q25.3×2 hmz [0.5], 21q22.12q22.3×3 [0.3] | |||||
8 | m | 41 | B-I | 46,XY,t(4;11)(q21;q23)[3] | 1p31.1p31.1×2hmz, 5q23.1q23.1x2 hmz | 98% t(4;11)(q21;q23) |
n/rvl t(9;22)(q34;q11) | ||||||
9 | f | 29 | B-II | 56,XX,+X,+4,+4,+6,+10,+14,+17,+18,+21, | (X)×3, (4)×5, (6)×3, (10)×3, | n/rvl t(9;22)(q34;q11); t(11q23)/MLL |
+21[18]/46,XX [2] | 11p11.2p11.12×2 hmz, (14) ×3, (17) ×3, (18) ×3, (21) ×5 | |||||
10 | m | 53 | B-I | 46,XY,t(4;11)(q21;q23) [20] | 2q36.3q37.1×2 hmz, 4q12q13.2×2 hmz, | 88% t(11q23)/MLL |
9p24.3p13.3×2 hmz, 9p21.3×1 | ||||||
12 | f | 36 | B-II | 46,XX,add(14)(q32) or t(14;?)(q32;?) | 14q31.2q32.33×3 | 92% t/del14q32/IGH(telomeric part); |
n/rvl t(9;22)(q34;q11); t(11q23)/MLL t(12p13)/ETV6 | ||||||
13 | m | 20 | BIII/BIV | 52~54,XY,+X,+4,+8,+14,+14,+18,+21, | (X) ×2 [0.83], (4) ×3, 6q15q23.1×1[0.36], (8) ×3, 9p21.3×0, 9p21.3p21.2×1, 9q22.33q31.1×1, 11q22.3×1, 13q14.2q31.1×1, (14) ×3, (18)x3, (21) ×3 | 94% +cMYC/8q24 |
+mar[cp16]/46,XY [4] | n/rvl t(8q24)/cMYC; t(11q23)/MLL; t(9;22)(q34;q11) | |||||
14 | m | 22 | B-II | 56,XY,+X,+Y,+4,+6,+8,+10,+14,+17,+18, | (X,Y)x1,(1-22)x2 | n/rvl t(9;22)(q34;q11); t(11q23)/MLL |
+21[9]/46,XY [11] | ||||||
15 | m | 19 | B-II | 54~56<2n>,XY,+X,+4,+6,+9,+10,+14,+15,+17,+21,+21[cp13]/ | (X)×2 [0.81], 3p21.31p21.1×2 hmz, (4) ×3 [0.72], (6)×3 [0.69], (9)×3 [0.42], (10)×3, (14)×3, (17)×3, (18)×3, 19p13.3p13.3×1 [0.4], | 30% +ABL/9q34 |
54~56,idem,add(19)(p?q?)[5]/46,XY [2] | 19p13.2p13.12×3 [0.3], (21) ×5 | n/rvl t(9;22)(q34;q11) t(11q23)/MLL | ||||
16 | m | 20 | B-II | 52~54,XY,+X,+4,+6,+?10,+17,+18,+20,+21,+mar[cp5]/ 52~54, XY, +X, dup(1)(q3?1q44),+4,+6,+?10, +17, +18, +20, +21[cp3]/46,XY [5 ] | (X)×2 [0.78], (4)×3, (6)×3, (10)×3, (17)×3, (18)×5,(21)×3 | n/rvl t(9;22)(q34;q11); t(11q23)/MLL |
17 | m | 22 | B-II | 46,XY [20] | (2)×1, (3)×1, (4)×1, (7)×1, (9)×1, (12)×1, (13)×1, (16)×1, (17)×1, (20)×1 | n/d |
18 | f | 28 | B-II | 46,XX,der(19)t(1;19)(q23;p13), inc[cp15]/ | 1q21.1q23.3×3 [0.7], 1q23.3q43×5 [0.5], 1q43q44×4 [0.6], | 28% t/del (19p13)/E2A (telomeric part) |
46,XX [5] | 9p24.3p12x1 [0.31], 19p13.3x1 | |||||
19 | m | 44 | B-II | 36,X,-Y,-2,-3,der(4),-7,der(12),-13,-15,-16,-17, -20x2,-22, +mar[cp6]/46,XY [14] | (Y) ×0 [0.8], (2) ×1, (3) ×1, 4q26q26×2 hmz, 5p13.2p13.1×1, (7)x1, 11q13.3q25×3, 12p13.33p11.22×1, 13q12.11q22.3×1, 13q22.3q34×1 [0.2], | 96% del (22q11)/BCR |
(15) ×1,(16) ×1,(17) ×1,18q11.2×3,(20) ×1,(22) ×1 | n/rvl t(9;22)(q34;q11) | |||||
21 | f | 46 | B-II | 46,X,-X, | (X) ×1 [0.1], 1p36.13p34.31×1 [0.2],1q23.3q44×3, 3q13.12q13.2×1 [0.5],4q21.22q28.1×1 [0.2], 4q35.1q35.2×1 [0.2],5q11.2q12.1×1 [0.2], 6q11.1q21×1 [0.5],6q22.32q22.33×2 hmz, 6q24.3q25.1×1 [0.5],6q25.3q27×1 [0.5], 8q11.1q11.21×2 hmz,9p24.3p24.2×0 [0.3],9p24.1p21.3×1, 9p21.3p21.3×0 [0.3], 9p21.3p11.2×1,9q21.11q34.3×3, 13q12.11q12.12×1 [0.5],13q13.3q31.1×1 [0.5], 18p11.32p11.31×1 [0.5],19p13.3×1,(21) ×3 | n/d |
add(1)(p3?3),-4, | ||||||
i(9)(q10), | ||||||
der(19)t(1;19)(q23;p13),+?21,+mar [15]/ | ||||||
46,XX [5] | ||||||
22 | f | 44 | B-II | 46,XX[29]/ | 7q35q36.2×1 [0.3],9p21.3p21.2×1 [0.4] | n/rvl t(9;22)(q34;q11) |
47,XX,+12[1] | ||||||
23 | f | 39 | B-II | 52~54,?XX,+?6,+?11,+?17,+?18,+?20,+?21, | (X) ×3,(4) ×3,(6) ×3,(8) ×3, 9p24.3p13.1×2 hmz,9p21.3p21.3×0 [0.5],(10) ×3,(14) ×3, | n/rvl t(9;22)(q34;q11) |
inc[cp3]/46,XX [12] | 14q23.1q23.2×2 hmz,(17) ×3,(18) ×3,(21) ×5 | |||||
24 | f | 36 | B-II | 44-45, X, -X,der(2),der(3),der(5),der(7),der(17),add(p11),+mar[cp5]/ | Xp22.33p22.32×1 [0.37], 2p13.1p12×1 [0.31], 3p24.1p22.3×1 [0.27], 3q13.12q13.13×1 [0.42], 5q11.2q12.1×1 [0.26], 5q13.3q14.1×1 [0.31], 7p12.2p12.1×1 [0.44], 13q14.2q14.3×1 [0.2], 17p13.3p11.1×1 [0.35] | n/rvl t(11q23)/MLL, t(9;22)(q34;q11 |
46,XX [15] | ||||||
25 | m | 26 | B-II | 45,XY,-7,der(14) t(7;14)(q11;q?32), del(17)(p10)[6]/ | 2p11.2p11.2×1, 7p14.1p11.2×1 [0.16], 7q34×0, 9p24.3p13.2×2 hmz, 9p21.3×0,16p13.3×1, 17p13.3p11.2×1 | 90% del (17p13)/TP53; |
46,XY [14] | n/rvl t(9;22)(q34;q11); t(14q32)/IgH; t(11q23)/MLL | |||||
26 | f | 38 | B-II | 46,XY [20] | 5 q14.3q14.3×2 hmz | n/rvl t(11q23)/MLL; t(9;22)(q34;q11) |
27 | m | 23 | B-I | 46,XY,der(19)[20] | (X,Y) ×1,(1-22) ×2 | n/rvl t(9;22)(q34;q11); t(11q23)/MLL; t(19p13)/ E2A |
28 | f | 23 | B-II | 46,XX,add(1)(q44),der(9), inc [9]/46,XX [11] | 1q21.1q32.1×3, 6q16.2q16.3×2 hmz, 9q21.13q31.1×1, 11q22.1q22.3×2 hmz | n/rvl t(9;22)(q34;q11) |
29 | m | 42 | B-II | 46,XY [13] | 11p11.2p11.12×2 hmz, 21q21.1q21.3×2 hmz | n/rvl t(11q23)/MLL; t(9;22)(q34;q11) |
30 | m | 21 | B-II | 57,XY,+X,+4,+6,+8,+10,+14,+17,+18,+21x2,+mar[14] | (X)×2 [0.81],(Y)×0 [0.13],(4)×3, (6)×3,(8)×3,(9)×3 [0.19],(10)×3,(14)×3,(17) ×3,(18) ×3,(21)×4 | 20% +ABL/9q34 |
n/rvl t(9;22)(q34;q11) t(11q23)/MLL | ||||||
31 | f | 47 | B-II | 46,XX,del(9)(p?21)[5]/46,XX[15] | 2q36.1×1,3q26.32q26.32×0, 3q26.32q26.33×1 | 11% del(9p21)/ CDKN2A |
n/rvl t(9;22)(q34;q11) | ||||||
32 | f | 24 | B-II | 46, XX [20] | (1q)×3 [0.19],(2)×1 [0.16],(3)×1 [0.15],(7)×1 [0.15],(8)×3 [0.15], 9p24.3q22.32×3 [0.12],9q22.32q34.3×1 [0.17],(10)×3 [0.43] (11)×3 [0.15],(12) ×1 [0.18],(13)×1 [0.15],(14)×3 [0.2],(15)×1 [0.18],(16)×1 [0.15], (18p)×3 [0.46],(18q)×3 [0.25],19p13.3p13.11×3 [0.15], 19p13.11q13.43×1 [0.2],(21)×3 [0.19] | 5% +MLL/11q23 |
n/rvl t(9;22)(q34;q11) t(11q23)/MLL | ||||||
34 | f | 44 | B-II | 46,XY,der(9),add(13)(p11),add(15)(p11), | 2q32.3q33.1×2 hmz,9p24.3×3,(21)×3 [0.15] | n/rvl t(9;22)(q34;q11); t(11q23)/MLL |
der(17) or mar,der(22) or mar,inc[9]/46,XY[2] | ||||||
35 | f | 40 | B-II | 46,XX [20] | (X,1-22)×2 | n/rvl t(9;22)(q34;q11); t(11q23)/MLL; |
36 | f | 30 | B-II | ?54-55,XX,?+4,+8,?+8 or 10,+9,+11,+?14,+21,+21,+mar[cp6]/46,XX[19]. | (X,1-22)×2 | 90%+ MLL (11q23), +ABL (9q34) |
n/rvl t(11q23)/MLL; t(9;22)(q34;q11) | ||||||
37 | m | 27 | B-II | 46,der(X),Y,del(6)(q22), ?der(16)[20] | 6p21.1×1, 6q14.3q22.31×1,6q25.2q25.3×1, 12p13.2p13.1×1,19q12×1, 19q13.11×1 | n/rvl t(9;22)(q34;q11); t(11q23)/MLL |
38 | f | 38 | B-II | 46,XX[20] | 2p11.2×1, 3p14.3×0, 12q13.12×1, 21q21.1×1 | n/rvl t(9;22)(q34;q11) |
39 | m | 41 | B-I | 34~38,XY, | (3) ×1 [0.5], (4) ×1 [0.5], (5) ×1 [0.5],6p22.2p21.32×2 hmz,(7) ×1 [0.5],(9) ×1 [0.5], 11q14.1q25×3 [0.6],(15) ×1 [0.5],(16) ×1 [0.5],(17) ×1 [0.5],(20) ×1 [0.5] | n/d |
+2-3mar[12]/46,XY[8] |
N° Pat | Locus | Genes Affected by Biallelic/Homozygous Deletion | Nature of Loss |
---|---|---|---|
38 | 3p14.3 | FLNB | biallelic |
31 | 3q26.32 | TBL1XR1, KCNMB2 | biallelic |
25 | 7q34 | TCAF2, PRSS1, PRSS2 | biallelic |
25 | 9p21.3 | MTAP, CDKN2A, CDKN2B-AS1, CDKN2B, DMRTA1 | homozygous |
13 | 9p21.3 | IFNB1, IFNW1, IFNA21, IFNA4, IFNA7, IFNA10, IFNA16, IFNA17, IFNA14, IFNA5, KLHL9, IFNA6, IFNA13, IFNA2, IFNA8, IFNA1, MIR31HG, IFNE, MIR31, MTAP, CDKN2A, CDKN2B-AS1, CDKN2B, DMRTA1, ELAVL2, IZUMO3 | biallelic |
23 | 9p21.3 | MTAP, CDKN2A, CDKN2B-AS1, CDKN2B, DMRTA1 | homozygous |
3 | 9p21.3 | CDKN2A, CDKN2B-AS1, CDKN2B, DMRTA1, ELAVL2 | homozygous |
21 | 9p21.3 | DMRTA1 | biallelic |
21 | 9p24.3 | DOCK8, KANK1, DMRT1, DMRT3, DMRT2, SMARCA2, VLDLR, KCNV2, PUM3, RFX3, GLIS3, SLC1A1 | biallelic |
Gene 1 | Chr. Location | Count of Event | Type of Events |
---|---|---|---|
CDKN2A/B | 9p21. 3 | 15 | 4loss0/8loss/3gain |
DMRTA | 9p21.3 | 15 | 4loss0/6loss/2cnLOH/3gain |
DOCK8 | 9p24.3 | 15 | 1loss0/5loss/4cnLOH/5gain |
TP53 | 17p13.1 | 13 | 7loss/6gain |
SMARCA2 | 9p24.3 | 13 | 6loss/4cnLOH/3gain |
PAX5 | 9p13 | 12 | 6loss/ 3cnLOH/ 3gain |
XPA; FOXE1; HEMGN | 9q22.33 | 12 | 7loss/1cnLOH/4gain |
USP45 | 6q16.2 | 12 | 4loss/1cnLOH/7gain |
RUNX1 | 21q22.2 | 11 | 7 gain/1gainX4/3gainX5 |
NF1 | 17q11.2 | 11 | 5loss/ 1cnLOH/ 5gain |
IGF2BP1 | 17q21.32 | 10 | 4loss/1cnLOH/5gain |
ERG; TMPRSS2 | 21q22.2 | 9 | 5gain/1gain4x/3gain5x |
CRLF2 | Xp22.23 | 9 | 4loss/ 5gain |
FGFR3 | 4p16.3 | 9 | 2loss/7gain |
FLNB | 3p14.3 | 8 | 7 loss/1 cnLOH |
IKZF1 | 7p12.2 | 8 | 8 loss |
RUNX2 | 6p21.1 | 8 | 1loss/7gain |
ARID1B | 6q25.3 | 8 | 1loss/7gain |
CIP2A | 3q13.13 | 7 | 7 loss |
PIK3CA | 3q26.32 | 7 | 6loss/1gain |
ATM | 11q22.3 | 6 | 3loss/3gain |
RB1 | 13q14.2 | 6 | 6 loss |
BIRC3 | 11q22.3 | 6 | 2loss/1cnLOH/3gain |
MYC | 8q24.21 | 6 | 6gain |
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Risinskaya, N.; Gladysheva, M.; Abdulpatakhov, A.; Chabaeva, Y.; Surimova, V.; Aleshina, O.; Yushkova, A.; Dubova, O.; Kapranov, N.; Galtseva, I.; et al. DNA Copy Number Alterations and Copy Neutral Loss of Heterozygosity in Adult Ph-Negative Acute B-Lymphoblastic Leukemia: Focus on the Genes Involved. Int. J. Mol. Sci. 2023, 24, 17602. https://doi.org/10.3390/ijms242417602
Risinskaya N, Gladysheva M, Abdulpatakhov A, Chabaeva Y, Surimova V, Aleshina O, Yushkova A, Dubova O, Kapranov N, Galtseva I, et al. DNA Copy Number Alterations and Copy Neutral Loss of Heterozygosity in Adult Ph-Negative Acute B-Lymphoblastic Leukemia: Focus on the Genes Involved. International Journal of Molecular Sciences. 2023; 24(24):17602. https://doi.org/10.3390/ijms242417602
Chicago/Turabian StyleRisinskaya, Natalya, Maria Gladysheva, Abdulpatakh Abdulpatakhov, Yulia Chabaeva, Valeriya Surimova, Olga Aleshina, Anna Yushkova, Olga Dubova, Nikolay Kapranov, Irina Galtseva, and et al. 2023. "DNA Copy Number Alterations and Copy Neutral Loss of Heterozygosity in Adult Ph-Negative Acute B-Lymphoblastic Leukemia: Focus on the Genes Involved" International Journal of Molecular Sciences 24, no. 24: 17602. https://doi.org/10.3390/ijms242417602