Impact of Additional Chromosomal Aberrations on the Disease Progression of Chronic Myelogenous Leukemia

Abstract

The emergence of additional chromosomal abnormalities (ACAs) in Philadelphia chromosome/BCR-ABL1 positive chronic myeloid leukemia (CML), is considered to be a feature of disease evolution. However, their frequency of incidence, impact on prognosis and treatment response effect in CML is not conclusive. In the present study, we performed a chromosome analysis of 489 patients in different clinical stages of CML, using conventional GTG-banding, Fluorescent in situ Hybridization and Spectral Karyotyping. Among the de novo CP cases, ACAs were observed in 30 patients (10.20%) with lowest incidence, followed by IM resistant CP (16.66%) whereas in AP and BC, the occurrence of ACAs were higher, and was about 40.63 and 50.98%, respectively. The frequency of occurrence of ACAs were compared between the study groups and it was found that the incidence of ACAs was higher in BC compared to de novo and IM resistant CP cases. Likewise, it was higher in AP patients when compared between de novo and IM resistant CP cases, mirroring the fact of cytogenetic evolution with disease progression in CML. In addition, we observed 10 novel and 10 rare chromosomal aberrations among the study subjects. This study pinpoints the fact that the genome of advanced phase patients was highly unstable, and this environment of genomic instability is responsible for the high occurrence of ACAs. Treatment response analysis revealed that compared to initial phases, ACAs were associated with an adverse prognostic effect during the progressive stages of CML. This study further portrayed the cytogenetic mechanism of disease evolution in CML.

Keywords: GTG-banding; Philadelphia Chromosome; Spectral Karyotyping; additional chromosomal aberrations; blast crisis; chronic myeloid leukemia; fluorescent in situ hybridization; variant Ph translocation.

Figure 1

Novel chromosomal aberrations identified in de novo CP CML patients (A). (i) G-banded karyotype showing 46,XX,t(9;22)(q34;q11),t(11;15)(p12;q15). (ii) Partial spectral karyotype confirming t(11;15)(p12;q15). (B) (i) G-banded karyotype showing 45,XY,t(9;22)(q34;q11),der(13;13)(q10;q10). (ii) Spectral karyotype, and (iii) Partial spectral karyotype confirming der(13;13)(q10;q10).

Figure 2

Novel chromosomal aberrations identified in CML AP patients (A) (i) G-banded karyotype showing 46,XX,t(9;22)(q34;q11),r(10)(p15q26). (ii) Spectral karyotype (iii) partial G-banded karyotype, and (iv) partial spectral karyotype confirming r(10)(p15q26). (B) (i) G-banded karyotype showing 46,XY,t(9;22)(q34;q11),ins(11;18)(p15;q21q23). (ii) Spectral karyotype (iii) partial spectral karyotype confirming ins(11;18)(p15;q21q23).

Figure 3

Novel chromosomal aberrations identified in CML BC patients (A) (i) G-banded karyotype showing 46,XY,inv(2)(p14q21),t(9;22)(q34;q11). (ii) Metaphase FISH using WCP-2 along with BCR-ABL1 DCDF translocation probe confirmed the absence of genetic material exchange of chromosome 2 with other chromosomes. (iii) Partial G-banded karyotype showing pericentric inversion of chromosome 2. (B) (i) G-banded karyotype showing 46,X,t(X;4)(q21;q34),t(9;22)(q34;q11). (ii) Spectral karyotype confirming t(X;4)(q21;q34). (C) (i) G-banded karyotype showing 49,XY,der(1)t(1;17)(p36.3;q25),+6,t(9;22)(q34;q11),+der(17)t(6;17)(q22;q25)×2. (ii) Confirmation of the complex karyotype by using Spectral karyotyping. (D) (i) G-banded karyotype showing 47,XY,der(7)t(7;9)(p11.2;q11)t(9;22) (q34;q11),der(9)t(1;9)(q32;q11),+mar. (ii) Confirmation of the complex karyotype by using Spectral karyotyping. (E). (i) G-banded karyotype showing 44,XY,der(7)t(5;7)(q21;p11.2),t(9;22)(q34;q11),-10,-19. (ii) Confirmation of the complex karyotype by using Spectral karyotyping.

Figure 4

Novel chromosomal aberrations identified in IM resistant CML CP patients. (i) G-banded karyotype showing 46,XX,t(9;22;16)(q34;q11;p11.2). (ii) Metaphase FISH confirmation of t(9;22;16)(q34;q11;p11.2) by DCDF BCR-ABL1 probe and CBFβ-MYH break apart probe, which detected two red (ABL1 genes on chr.9 and der chr.9), one green (BCR gene on chr.22), two red-yellow-green (BCR-ABL1 fusion gene on der(22) and CBFβ-MYH fusion gene on chr.16) signals. One red-yellow-green (CBFβ-MYH fusion gene) and green (BCR) signals together in the chromosome indicated derived chromosome16.

Figure 5

The frequency of incidence of ACAs among the study groups. Bar graph showing the frequency of incidence of additional chromosomal aberrations in different clinical stages of CML (***P < 0.001, **P < 0.01).