Alterations of<i>P53</i>and<i>RB</i>Genes and the Evolution of the Accelerated Phase of Chronic Myeloid Leukemia

Beck, Zoltán; Kiss, Attila; Tóth, Ferenc; Szabó, Judit; Bácsi, Attila; Balogh, Erzsébet; Borbély, Ágnes; Telek, B; Kovács, Eszter; Oláh, Éva; Rák, K.

doi:10.3109/10428190009059278

Cited by 42 publications

(22 citation statements)

References 39 publications

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“…A number of tumor suppressor genes are inactivated or downregulated by BCR-ABL in Ph + leukemia, including protein phosphatase 2 (21), p53 (22) and phosphatase and tensin homolog (23). The results of the present study revealed that the tumor suppressor, PDCD4, is also downregulated in CML patients and is negatively correlated with BCR-ABL expression.…”

Section: Discussionsupporting

confidence: 48%

Programmed cell death 4 and BCR-ABL fusion gene expression are negatively correlated in chronic myeloid leukemia

et al. 2016

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Abstract. Programmed cell death 4 (PDCD4) is a tumor suppressor that inhibits carcinogenesis, tumor progression and invasion by preventing gene transcription and translation. Downregulation of PDCD4 expression has been identified in multiple types of human cancer, however, to date, the function of PDCD4 in leukemia has not been investigated. In the present study, PDCD4 mRNA and protein expression was investigated in 50 patients exhibiting various phases of chronic myeloid leukemia (CML) and 20 healthy individuals by reverse transcription-quantitative polymerase chain reaction and western blot analysis. PDCD4 expression and cell proliferation was also investigated following treatment with the tyrosine kinase inhibitor, imatinib, in K562 cells. The results demonstrated that PDCD4 mRNA and protein expression was decreased in all CML samples when compared with healthy controls, who expressed high levels of PDCD4 mRNA and protein. No significant differences in PDCD4 expression were identified between chronic phase, accelerated phase and blast phase CML patients. In addition, PDCD4 expression was negatively correlated with BCR-ABL gene expression (r=-0.6716; P<0.001). Furthermore, K562 cells treated with imatinib exhibited significantly enhanced PDCD4 expression. These results indicate that downregulation of PDCD4 expression may exhibit a critical function in the progression and malignant proliferation of human CML.

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Section: Discussionsupporting

confidence: 48%

Programmed cell death 4 and BCR-ABL fusion gene expression are negatively correlated in chronic myeloid leukemia

et al. 2016

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“…Some tumor suppressor genes have been shown to be inactivated or down-regulated by BCR-ABL in Ph ϩ leukemia, including PP2A, 34 p53, 35 RB, 35 and interferon consensus sequence-binding protein. 36 In this study, we show that the tumor suppressor Pten is also down-regulated by BCR-ABL and that overexpression of Pten BLOOD, 21 JANUARY 2010 ⅐ VOLUME 115, NUMBER 3 For personal use only.…”

Section: Discussionmentioning

confidence: 99%

PTEN is a tumor suppressor in CML stem cells and BCR-ABL–induced leukemias in mice

Peng

Chen

Yang

et al. 2010

Blood

108

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IntroductionThe human Philadelphia chromosome (Ph) arises from a reciprocal translocation between chromosome 9 and 22, resulting in the formation of chimeric BCR-ABL oncogene. BCR-ABL encodes a constitutively activated, oncogenic tyrosine kinase. 1 Ph ϩ leukemia induced by BCR-ABL includes chronic myeloid leukemia (CML) and B-cell acute lymphoid leukemia (B-ALL). The BCR-ABL kinase inhibitor imatinib mesylate induces a complete hematologic and cytogenetic response in the majority of chronic-phase CML patients 2 but is unable to completely eradicate BCR-ABLexpressing leukemic cells, 3,4 suggesting that leukemia stem cells are not eliminated. Over time, patients frequently become drugresistant and develop progressive disease despite continued treatment. [5][6][7] Moreover, B-ALL is less sensitive to imatinib, suggesting that inhibition of BCR-ABL kinase activity is not enough to suppress B-ALL development. New therapeutic strategies need to be developed for Ph ϩ leukemia.Tumors progress to more advanced stages after acquiring additional genetic alterations, and inactivation of tumor suppressor genes are common in human cancers. Phosphatase and tensin homolog (PTEN) 8 is often deleted or inactivated in many tumor types, including glioblastoma, 9 endometrial carcinoma, 10 and lymphoid malignancies. 11 PTEN is a phosphatase that dephosphorylates phosphatidylinositol-3-trisphosphate. 12,13 Phosphatidylinositol-3-trisphosphate is a direct product of phosphoinositide 3-kinase (PI3K) activity and plays a critical role in the regulation of cell survival and growth by activating the Ser/Thr protein kinase PDK1 and its downstream target Akt. 14,15 Activated Akt mediates several well-described PI3K responses that include cell survival and growth, cellular metabolism, angiogenesis, and cell migration.Mice with a complete null mutation of Pten develop early embryonic lethality at E9.5. [16][17][18] Pten-heterozygous mice die within 1 year after birth, and survivors develop a broad range of tumors, including mammary, thyroid, endometrial, and prostate cancers, [16][17][18] as well as autoimmunity related to Fas-mediated response. 19 Mice with the tissuespecific deletion of Pten using the Cre-loxP system have become available for studying physiologic functions of Pten in adult tissues and organs. 20,21 For example, mice with Pten deletion in adult hematopoietic cells develop and die of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). 22 Akt1 is a major downstream signaling molecule of PTEN and is activated after PTEN is mutated in human cancers. Investigators in a recent study 23 showed that the deficiency of Akt1 is sufficient to suppress the development of several types of tumors in Ptenheterozygous mice, including prostate cancer, endometrial carcinoma, thyroid neoplasia, intestinal polyps, and lymphoid hyperplasia. Moreover, rapamycin, which directly inhibits the Akt downstream molecule mammalian target of rapamycin (mTOR), effectively inhibits survival and proliferation of AML cells from PTEN fl/fl ;Mx-1...

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“…[161][162][163] A unifying mechanism for disease progression in CML As discussed, CML-BC is characterized by several seemingly incoherent chromosomal and molecular abnormalities. Yet, some generalizations can be attempted: (1) the vast majority of secondary changes involve genes encoding nucleus-localized proteins that directly or indirectly regulate gene transcription; (2) mutations/loss of function of tumor suppressor genes is predominant over mutation/activation of oncogenes; and (3) p53 is genetically or functionally inactivated in a large fraction of CML-BC cases.…”

Section: Role Of Molecular Abnormalities In CML Disease Progressionmentioning

confidence: 99%

The biology of CML blast crisis

Calabretta

Perrotti²

2004

Blood

508

443

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Chronic myelogenous leukemia (CML) evolves from a chronic phase characterized by the Philadelphia chromosome as the sole genetic abnormality into blast crisis, which is often associated with additional chromosomal and molecular secondary changes. Although the pathogenic effects of most CML blast crisis secondary changes are still poorly understood, ample evidence suggests that the phenotype of CML blast crisis cells (enhanced proliferation and survival, differentiation arrest) depends on cooperation of BCR/ABL with genes dysregulated during disease progression. Most genetic abnormalities of CML blast crisis have a direct or indirect effect on p53 or Rb (or both) gene activity, which are primarily required for cell proliferation and survival, but not differentiation. Thus, the differentiation arrest of CML blast crisis cells is a secondary consequence of these abnormalities or is caused by dysregulation of differentiation-regulatory genes (ie, C IntroductionBlast crisis is the terminal phase of chronic myelogenous leukemia (CML), a clonal myeloproliferative disorder of the hematopoietic stem cell that typically evolves in 3 distinct clinical stages: chronic and accelerated phases and blast crisis. 1,2 The chronic phase lasts several years and is characterized by accumulation of myeloid precursors and mature cells in bone marrow, peripheral blood, and extramedullary sites. 1,2 The accelerated phase lasts 4 to 6 months and is characterized by an increase in disease burden and in the frequency of progenitor/precursor cells rather than terminally differentiated cells. The blast crisis lasts only a few months and is characterized by the rapid expansion of a population of myeloid or lymphoid differentiation-arrested blast cells. 3 CML is consistently associated with an acquired genetic abnormality, the Philadelphia chromosome (Ph 1 ), a shortened chromosome 22 resulting from a reciprocal translocation of the long arms of chromosomes 9 and 22. 4,5 This translocation generates the BCR/ABL fusion gene, which is translated in the p210 BCR/ABL oncoprotein 6,7 of almost all patients with CML.Two other BCR/ABL proteins, p190 and p230, generated by variant fusion genes, are only occasionally detected in classic CML. 8 Expression of p210 BCR/ABL is necessary and sufficient for malignant transformation, as demonstrated in in vitro assays and leukemogenesis in mice. [9][10][11][12][13] Transition to blast crisis is the unavoidable outcome of CML except in a cohort of patients receiving allogeneic bone marrow transplants early in the chronic phase. 14 The development of the BCR/ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec; formerly STI571; Novartis, Basel, Switzerland) as the treatment of choice for chronic-phase CML and its remarkable therapeutic effects suggest that blast crisis transition will be postponed for several years in most patients with CML. 15,16 However, the persistence of BCR/ABL transcripts in a cohort of patients with complete cytogenetic response raises the possibility that treatment with imatini...

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Alterations ofP53andRBGenes and the Evolution of the Accelerated Phase of Chronic Myeloid Leukemia

Cited by 42 publications

References 39 publications

Programmed cell death 4 and BCR-ABL fusion gene expression are negatively correlated in chronic myeloid leukemia

Programmed cell death 4 and BCR-ABL fusion gene expression are negatively correlated in chronic myeloid leukemia

PTEN is a tumor suppressor in CML stem cells and BCR-ABL–induced leukemias in mice

The biology of CML blast crisis

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