Heterogeneous BCR-ABL1 signal patterns identified by fluorescence in situ hybridization are associated with leukemic clonal evolution and poorer prognosis in BCR-ABL1 positive leukemia

Zhang, Zhanglin; Chen, Zhiwei; Jiang, Mei; Liu, Shuyuan; Guo, Yang; Wan, Lei; Li, Fēi

doi:10.1186/s12885-019-6137-8

Cited by 7 publications

(8 citation statements)

References 23 publications

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“…In recent decades, a high number of biological studies have been done to elucidate the molecular mechanisms of CML pathogenesis and progression [ 16 , 17 , 18 ]. The results of these studies were fundamental to understand how and why the p210 tyrosine kinase protein is able to drive the leukemic transformation of Ph+ hematopoietic progenitors by altering cell proliferation, apoptosis, adhesion and inducing genomic instability [ 1 , 2 ].…”

mentioning

confidence: 99%

Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives

Russo

Garcia-Gutierrez

Soverini

et al. 2020

JCM

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Ph+ chronic myeloid leukemia (CML) is a clonal myeloproliferative disease whose clinical course is characterized by progression disease from the early chronic phase (CP) to the fatal blastic phase (BP). This programmed course is closely related to the translocation t(9;22)(q22;q11) and the resulting BCR-ABL1 fusion protein (p210) that drives the leukemic transformation of hematopoietic stem cells. Therefore, the cure of CML can only pass through the abrogation of the Ph+ clone. Allogeneic stem cell transplantation (allo-SCT) and interferon-alpha (IFNα) have been proven to reduce the Ph+ clone in a limited proportion of CML population and this translated in a lower rate of progression to BP and in a significant prolongation of survival. Tyrosine-kinase inhibitors (TKIs), lastly introduced in 2000, by preventing the disease blastic transformation and significantly prolonging the survival in up to 90% of the patient population, radically changed the fate of CML. The current therapy with TKIs induces a chronicization of the disease but several criticisms still persist, and the most relevant one is the sustainability of long-term therapy with TKIs in terms of compliance, toxicity and costs. The perspectives concern the optimization of therapy according to the age, the risk of disease, the potency and the safety profiles of the TKIs. The prolongation of survival is the most important end point which should be guaranteed to all patients. The treatment free remission (TFR) is the new goal that we would like to give to an increasing number of patients. The cure remains the main objective of CML therapy.

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confidence: 99%

Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives

Russo

Garcia-Gutierrez

Soverini

et al. 2020

JCM

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“…Among the confirmed fusions, several entries were also previously published in the scientific reports. Among them are BCR-ABL1 , known as Philadelphia chromosome, which is the first characterized cancer chimeric transcript which is frequently found in leukemias [ 36 ]; detected here in acute lymphoblastic leukemia. CCDC6-RET is the most common RET fusion in papillary thyroid cancer, which was also identified in lung cancer, acute lymphoblastic leukemia, and other cancers [ 37 ]; detected here in breast fibrosarcoma.…”

Section: Resultsmentioning

confidence: 99%

Experimentally Deduced Criteria for Detection of Clinically Relevant Fusion 3′ Oncogenes from FFPE Bulk RNA Sequencing Data

Rabushko

Suntsova

Seryakov³

et al. 2022

Biomedicines

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Drugs targeting receptor tyrosine kinase (RTK) oncogenic fusion proteins demonstrate impressive anti-cancer activities. The fusion presence in the cancer is the respective drug prescription biomarker, but their identification is challenging as both the breakpoint and the exact fusion partners are unknown. RNAseq offers the advantage of finding both fusion parts by screening sequencing reads. Paraffin (FFPE) tissue blocks are the most common way of storing cancer biomaterials in biobanks. However, finding RTK fusions in FFPE samples is challenging as RNA fragments are short and their artifact ligation may appear in sequencing libraries. Here, we annotated RNAseq reads of 764 experimental FFPE solid cancer samples, 96 leukemia samples, and 2 cell lines, and identified 36 putative clinically relevant RTK fusions with junctions corresponding to exon borders of the fusion partners. Where possible, putative fusions were validated by RT-PCR (confirmed for 10/25 fusions tested). For the confirmed 3′RTK fusions, we observed the following distinguishing features. Both moieties were in-frame, and the tyrosine kinase domain was preserved. RTK exon coverage by RNAseq reads upstream of the junction site were lower than downstream. Finally, most of the true fusions were present by more than one RNAseq read. This provides the basis for automatic annotation of 3′RTK fusions using FFPE RNAseq profiles.

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“…Detection of BCR-ABL transcripts in patients with CML by quantitative reverse transcription-polymerase chain reaction (QR-PCR) is clinically important for determining the treatment response and selecting the optimal treatment strategy (as well as for providing prognostic information). 4,70 For example, leukemia cell lines expressing high levels of BCR-ABL are less sensitive to imatinib; when a response occurs, it is rarely sustained, and the development of refractoriness is often rapid because it yields mutant subclone resistance in chronic myeloid leukemia. 3 Furthermore, several "molecular response milestones" at specific time points might help predict the outcome and select treatment drugs.…”

Section: What Is a Better Methods Of Management? Bcr-abl Monitoring To Prevent The Onset Of CML Blast Crisis Transformationmentioning

confidence: 99%

Understanding and Monitoring Chronic Myeloid Leukemia Blast Crisis: How to Better Manage Patients

Wang¹,

Li²,

Chen³

et al. 2021

CMAR

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Chronic myeloid leukemia (CML) is triggered primarily by the t(9;22) (q34.13; q11.23) translocation. This reciprocal chromosomal translocation leads to the formation of the BCR-ABL fusion gene. Patients in the chronic phase (CP) experience a good curative effect with tyrosine kinase inhibitors. However, cases are treatment refractory, with a dismal prognosis, when the disease has progressed to the accelerated phase (AP) or blast phase (BP). Until now, few reports have provided a comprehensive description of the mechanisms involved at different molecular levels. Indeed, the underlying pathogenesis of CML evolution comprises genetic aberrations, chromosomal translocations (except for the Philadelphia chromosome), telomere biology, and epigenetic anomalies. Herein, we provide knowledge of the biology responsible for blast transformation of CML at several levels, such as genetics, telomere biology, and epigenetic anomalies. Because of the limited treatment options available and poor outcomes, only the therapeutic response is monitored regularly, which involves BCR-ABL transcript level assessment and immunologic surveillance, with the optimal treatment strategy for patients in CP adapted to evaluate disease recurrence or progression. Overall, selecting optimal treatment endpoints to predict survival and successful TFR improves the quality of life of patients. Thus, identifying risk factors and developing risk-adapted therapeutic options may contribute to a better outcome for advanced-phase patients.

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Heterogeneous BCR-ABL1 signal patterns identified by fluorescence in situ hybridization are associated with leukemic clonal evolution and poorer prognosis in BCR-ABL1 positive leukemia

Cited by 7 publications

References 23 publications

Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives

Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives

Experimentally Deduced Criteria for Detection of Clinically Relevant Fusion 3′ Oncogenes from FFPE Bulk RNA Sequencing Data

Understanding and Monitoring Chronic Myeloid Leukemia Blast Crisis: How to Better Manage Patients

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