Cytogenetic landscape and impact in blast phase of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy

Chen, Z.; Shao, Chenhui; Wang, W.; Zuo, Zhuang; Mou, Xiaozhou; Hu, Shimin; DiGiuseppe, Joseph A.; Zu, Youli; Medeiros, L. Jeffrey; Hu, Shimin

doi:10.1038/leu.2016.231

Cited by 36 publications

(36 citation statements)

References 46 publications

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“…Epigenetic silencing of negative regulators of the Wnt signaling cascade is also frequently observed in leukemias, including CML (80). Chromosomal aberations (81), alterations in the bone marrow microenvironment (82), as well as other mechanisms, may play significant roles in LSC resistance (for a recent review on CML LSC resistance please see T. Holyoake and D. Vetrie (83) ). β-Catenin signaling has also been reported to be activated during the development of MLL (mixed-lineage leukemia) leukemic stem cells(84).…”

Section: Wnt Signaling In CMLmentioning

confidence: 99%

CBP/Catenin antagonists: Targeting LSCs’ Achilles heel

Kim

Gang

Kahn

2017

Experimental Hematology

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Cancer Stem Cells (CSCs) including Leukemia Stem Cells (LSCs) exhibit self-renewal capacity and differentiation potential, and have the capacity to maintain or renew and propagate a tumor/leukemia. The initial isolation of CSCs/LSCs was in adult myelogenous leukemia, although more recently, the existence of CSCs in a wide variety of other cancers has been demonstrated. CSCs in general, and LSCs specifically in regards to this review, are responsible for initiation of disease, therapeutic resistance and ultimately disease relapse. One key focus in cancer research over the past decade has been to develop therapies to safely eliminate the LSC/CSC population. One major obstacle to this goal is the identification of key mechanisms that distinguish LSCs from normal endogenous hematopoietic stem cells. An additional daunting feature that has recently come to light with advances in next generation sequencing and single cell sequencing is the heterogeneity within leukemias/tumors, with multiple combinations of mutations, gain and loss of function of genes, etc. being capable of driving disease, even within the CSC/LSC population. The focus of this review/perspective will be on our work in identifying and validating in both CML and ALL, a safe and efficacious mechanism to target an evolutionarily conserved signaling nexus, which constitutes a common “Achilles Heel” for LSC/CSC, utilizing small molecule specific CBP/catenin antagonists.

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Section: Wnt Signaling In CMLmentioning

confidence: 99%

CBP/Catenin antagonists: Targeting LSCs’ Achilles heel

Kim

Gang

Kahn

2017

Experimental Hematology

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“…This phenomenon coincided with the current study. Moreover, one study reported that the emergence of the 3q26.2 rearrangement had a high frequency of correlation with BCR‐ABL1 mutations . However, other studies showed that ACAs and KD mutations were randomly combined in CML patients, representing different resistance mechanisms .…”

Section: Discussionmentioning

confidence: 99%

“…Although the use of tyrosine kinase inhibitors (TKIs) has greatly improved the management and prognosis of CML patients, research on CML has never stopped. Current studies have found that the incidence of additional chromosomal abnormalities (ACAs) is approximately 5% in the chronic phase (CP) of CML patients, 30% in the accelerated phase (AP) and 80% in the blast phase (BP) . Hence, ACAs are considered an intrinsic factor in the progression of CML patients with a negative impact on survival and prognosis .…”

Section: Introductionmentioning

confidence: 99%

Outcomes of 219 chronic myeloid leukaemia patients with additional chromosomal abnormalities and/or tyrosine kinase domain mutations

Xue

Cheng

Zhao

et al. 2018

Int J Lab Hematology

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Introduction To confirm the role of additional chromosomal abnormalities (ACAs) and kinase domain (KD) mutations in the progression and outcomes of Chronic myeloid leukaemia (CML) patients and the connection between them, we analysed the ACAs and KD mutations of 219 CML patients admitted to our hospital. Methods Cytogenetic analysis of metaphases was performed to detect ACAs, and the BCR‐ABL1 KD was sequenced to detect KD mutations. Results Twenty‐four patients (11.0%) had ACAs in addition to the BCR‐ABL1 or t(9;22)(q34;q11) translocation. The most common abnormality was trisomy 8. Twelve different KD mutations were observed in 13 out of 53 imatinib‐resistant patients (24.5%). p.(Y235H) (n = 3; 23.07%), p.(F359V) and p.(T315I) (n = 2; 15.38%) presented most frequently. KD mutations subtypes (p.(E255K), p.(T315I), p.(F359V), p.(M244V) and p.(L298V)) coexisted with ACAs. The incidence of CML progression was 12/22 (54.5%) in the group of patients with ACAs and/or KD mutations and 2/143 (1.4%) in the group of patients without ACAs or KD mutations (CI 95%, P < 0.001) and was higher in the KD mutations group than in the ACAs group (P = 0.046). The group of patients with ACAs and/or KD mutations had more men than the group of patients without ACAs or KD mutations (P = 0.013). Conclusion We conclude that ACAs and/or KD mutations are related to CML progression and are adverse outcome factors. Their presence exhibits gender differences and is more common in males. p.(E255K), p.(T315I), p.(F359V), p.(M244V) and p.(L298V) emerge more frequently when ACAs and KD mutations coexist.

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“…The results were reported with the 2016 International System for Human Cytogenetics Nomenclature as described previously . For patients with CML for whom BM biopsy was essential or helpful, the karyotype was stratified into groups with favorable, neutral, or poor cytogenetic risk according to findings reported previously …”

Section: Methodsmentioning

confidence: 99%

“…12 For patients with CML for whom BM biopsy was essential or helpful, the karyotype was stratified into groups with favorable, neutral, or poor cytogenetic risk according to findings reported previously. 2,13,14 BCR-ABL1 transcripts and cytogenetic studies were determined at diagnosis and every 3 months for a response assessment. BCR-ABL1 was detected by quantitative reverse transcriptase-polymerase chain reaction methods with RNA extracted from BM or PB samples as described elsewhere.…”

Section: Molecular and Cytogenetic Studiesmentioning

confidence: 99%

Bone marrow core biopsy in 508 consecutive patients with chronic myeloid leukemia: Assessment of potential value

Hidalgo-Lόpez

Kanagal‐Shamanna

Quesada

et al. 2018

Cancer

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BACKGROUND The diagnosis of chronic myeloid leukemia (CML) is based on characteristic clinical and laboratory findings and the presence of BCR/ABL1 in the blood and/or bone marrow (BM). The utility of BM core biopsy in the workup of patients with CML has been questioned. METHODS The potential added value of BM biopsy versus aspiration in the workup of a single‐institution series of 508 patients with CML at their initial presentation was systematically assessed. BM biopsy was considered essential when it was needed to establish the disease phase, often because blast counts derived from aspirate smears were misleading because the biopsy specimen was more representative of the disease. BM biopsy was considered helpful if it was needed for other nonessential reasons. RESULTS In 127 patients (25%), BM biopsy was either essential (109 patients) or helpful (18 patients). Patients with accelerated‐phase (AP) or blast‐phase (BP) disease often required a biopsy related to essential reasons. High‐grade myelofibrosis (MF) was more frequent in patients with AP/BP disease than patients with chronic‐phase disease (P = .0005), and the identification of BP disease required a BM biopsy assessment in 75% of the patients (P = .001). A follow‐up BM evaluation more often yielded inadequate aspirates in patients with inadequate BM aspirates at the time of their initial diagnosis. CONCLUSIONS BM core biopsy remains valuable in the workup of 25% of patients with CML because it facilitates identification of the disease phase or MF. The initial grade of MF is associated with the disease stage and outcome after therapy. BM biopsy is, therefore, indicated for patients with CML who have AP/BP disease or other findings suggestive of progressive disease.

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Cytogenetic landscape and impact in blast phase of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy

Cited by 36 publications

References 46 publications

CBP/Catenin antagonists: Targeting LSCs’ Achilles heel

CBP/Catenin antagonists: Targeting LSCs’ Achilles heel

Outcomes of 219 chronic myeloid leukaemia patients with additional chromosomal abnormalities and/or tyrosine kinase domain mutations

Bone marrow core biopsy in 508 consecutive patients with chronic myeloid leukemia: Assessment of potential value

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