The impact of gene profiling in chronic myeloid leukaemia

Yong, Agnes S. M.; Melo, Junia V.

doi:10.1016/j.beha.2009.04.002

Cited by 26 publications

(8 citation statements)

References 71 publications

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“…In support of this suggestion, expression studies revealed that BCR-ABL1 dramatically perturbs the CML transcriptome (31), resulting in altered expression of genes, some of which (e.g., PRAME, MZF1, EVI-1, WT1, and JUN-B) might play a role in BP (19,(32)(33)(34). Nonetheless, the posttranscriptional, translational, and posttranslational effects of high BCR-ABL1 levels result in the constitutive activation of factors with reported mitogenic, antiapoptotic, and antidifferentiation activity (e.g., MAPK ERK1/2 , MYC, JAK2, YES-1, LYN, hnRNP-E2, MDM2, STAT5, BMI-1, and BCL-2) and inhibition of major key regulators of cellular processes, such as those regulated by the tumor suppressors p53, CCAAT/enhancer binding protein-α (C/EBPα), and PP2A (19,29,35).…”

Section: Biological Complexity Of Cml-bpmentioning

confidence: 76%

Chronic myeloid leukemia: mechanisms of blastic transformation

Perrotti¹,

Goldman²,

Skórski³

2010

J. Clin. Invest.

359

367

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Section: Biological Complexity Of Cml-bpmentioning

confidence: 76%

Chronic myeloid leukemia: mechanisms of blastic transformation

Perrotti¹,

Goldman²,

Skórski³

2010

J. Clin. Invest.

359

367

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“…Our previously published biomarker data on the pCrKL/CrKL ratio and BCR-ABL1 transcript type can only predict patients likely to achieve a CCR and cannot predict patients destined to progress to BC. 3,19 Various techniques have been used on diagnostic chronic phase samples to predict who will develop BC, 29 and a variety of novel genomic lesions have been identified at BC. 30 It is however not possible at diagnosis to reliably predict which patients will develop disease progression.…”

Section: Discussionmentioning

confidence: 99%

Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression

Lucas

Harris

Giannoudis

et al. 2011

Blood

123

121

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Prospective identification of patients whose chronic myeloid leukemia (CML) will progress to blast crisis is currently not possible. PP2A is a phosphatase and tumor suppressor that regulates cell proliferation, differentiation, and survival. Cancerous inhibitor of PP2A (CIP2A) is a recently described inhibitor of PP2A in breast and gastric cancer. The aim of this study was to investigate whether CIP2A played a role in CML and whether PP2A or its inhibitor proteins CIP2A or SET could predict clinical outcome. At the time of diagnosis of CML, patients who will later progress to blast crisis have significantly higher levels of CIP2A protein (P < .0001) than patients who do not progress, suggesting that PP2A is functionally inactive. We show that the potential mechanism for disease progression is via altered phosphorylation of the oncogene c-Myc. Knockdown of CIP2A results in increased PP2A activity, decreased c-Myc levels, and a decrease in BCR-ABL1 tyrosine kinase activity. We demonstrate that CIP2A levels at diagnosis can consistently predict patients who will progress to blast crisis. The data show that CIP2A is biologically and clinically important in CML and may be a novel therapeutic target. (Blood. 2011;117(24):6660-6668) IntroductionChronic myeloid leukemia (CML) is a malignant disease of the primitive hematologic cell, characterized by inappropriate expansion of myeloid cells. Although this disease is readily controlled by imatinib, approximately one-third of patients will eventually fail treatment 1,2 ; and a significant proportion of these will progress toward blast crisis (BC), which is usually rapidly fatal. Poor response to imatinib and progression to BC have been linked to high BCR-ABL1 tyrosine kinase activity, 3 but why one patient can remain in well-controlled chronic phase for decades whereas another may rapidly progress to BC is poorly understood.The BCR-ABL1 tyrosine kinase in CML is responsible for growth and survival of the malignant cells through activation of signaling pathways, such as the mitogen-activated protein kinase cascade and the PI3K pathway. 4,5 A major cellular serine/threonine phosphatase working to down-regulate activation of these pathways is the tumor suppressor protein phosphatase 2A (PP2A). 6 In CML cells, PP2A is a key target of BCR-ABL1 signaling; this protein becomes inactivated in these cells because BCR-ABL1 stimulates prevention of its auto-dephosphorylation at tyrosine 307 . 7,8 Maintenance of pY 307 -PP2A levels in CML cells feeds back to BCR-ABL1 and facilitates increased and sustained kinase activity. Inhibition of BCR-ABL1 by imatinib results in reactivation of PP2A, inducing both suppression of growth and enhanced apoptosis of the leukemic cells. 8 However, it is unknown whether Y 307 in PP2A is a direct substrate of BCR-ABL1, and the mechanism regulating phosphorylation of PP2A at this site is not clearly defined.One proposal for the mechanism through which BCR-ABL1 regulates PP2A activity in CML cells involves expression of the PP2A inhibitor protein SET. In ...

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“…[14][15][16][17][18][19][20][21][22] Furthermore, gene expression changes may distinguish CP from BC and predict response to TKI therapy. [23][24][25][26][27] The increasingly mainstream use of next-generation sequencing for studying cancer genomes is advancing our understanding of disease pathogenesis and prognosis. [28][29][30][31][32] In CML, this technology may reveal the most pathologically relevant additional genetic events to identify highrisk patients and direct trials to test new combinational treatment approaches.…”

Section: Introductionmentioning

confidence: 99%

Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease

Branford

Wang

Yeung

et al. 2018

Blood

156

256

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Genomic events associated with poor outcome in chronic myeloid leukemia (CML) are poorly understood. We performed whole-exome sequencing, copy-number variation, and/or RNA sequencing for 65 patients to discover mutations at diagnosis and blast crisis (BC). Forty-six patients with chronic-phase disease with the extremes of outcome were studied at diagnosis. Cancer gene variants were detected in 15 (56%) of 27 patients with subsequent BC or poor outcome and in 3 (16%) of 19 optimal responders ( = .007). Frequently mutated genes at diagnosis were ,, and The methyltransferase was a novel recurrently mutated gene. A novel class of variant associated with the Philadelphia (Ph) translocation was detected at diagnosis in 11 (24%) of 46 patients comprising fusions and/or rearrangement of genes on the translocated chromosomes, with evidence of fragmentation, inversion, and imperfect sequence reassembly. These were more frequent at diagnosis in patients with poor outcome: 9 (33%) of 27 vs 2 (11%) of 19 optimal responders ( = .07). Thirty-nine patients were tested at BC, and all had cancer gene variants, including kinase domain mutations in 58%. However, mutations cooccurred with other mutated cancer genes in 89% of cases, and these predated mutations in 62% of evaluable patients. Gene fusions not associated with the Ph translocation occurred in 42% of patients at BC and commonly involved fusion partners that were known cancer genes (78%). Genomic analysis revealed numerous relevant variants at diagnosis in patients with poor outcome and all patients at BC. Future refined biomarker testing of specific variants will likely provide prognostic information to facilitate a risk-adapted therapeutic approach.

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The impact of gene profiling in chronic myeloid leukaemia

Cited by 26 publications

References 71 publications

Chronic myeloid leukemia: mechanisms of blastic transformation

Chronic myeloid leukemia: mechanisms of blastic transformation

Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression

Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease

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