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

Ramachandran Krishna Chandran,Hariharan Sreedharan,Kunnathur Murugesan Sakthivel,Narayanan Geetha,Raveendran Suresh Kumar,Kumarapillai Mohanan Nair Jagathnath Krishna

doi:10.3389/fonc.2019.00088

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.

Highlights

Chronic myelogenous leukemia (CML) is a hematopoietic disorder of multipotential stem cells, hallmarked by the cytogenetic event t(9;22)(q34;q11), and results in the generation of the Philadelphia (Ph) chromosome carrying BCR-ABL1 fusion gene, which plays a central role in the pathogenesis of CML (1–3)
Based on disease course and clinical characteristics, CML is often divided into the relatively indolent, early phase known as Chronic Phase (CP) and more aggressive advanced phase, consisting of an initial Accelerated Phase (AP) and a fatal Blast Crisis Phase (BC)
In 1960, Nowell and Hungerford discovered that a minute abnormal chromosome 22, called the Philadelphia Chromosome, remarked first time cancer with a specific genetic abnormality, which created a new era of genetic diagnosis (12)

Summary

Introduction

Chronic myelogenous leukemia (CML) is a hematopoietic disorder of multipotential stem cells, hallmarked by the cytogenetic event t(9;22)(q34;q11), and results in the generation of the Philadelphia (Ph) chromosome carrying BCR-ABL1 fusion gene, which plays a central role in the pathogenesis of CML (1–3). Survival rates are exceptionally high in CMLCP; therapy options for CML-AP and BC are very limited (4). This may be due to the biological complexity of the disease or the cascade of molecular events responsible for blastic transformation of CML, which remains inconclusive. The accumulation of additional non-random cytogenetic aberrancies in Ph positive cells, known as “clonal evolution,” is considered to be the reflection of genetic instability that characterizes disease evolution in CML. CML-BC patients unveiled much more complex karyotypes in comparison with other phases of CML (9, 10)

Methods

Results

Conclusion