Methylation-Independent Silencing of the Tumor Suppressor <i>INK4b</i> (p15) by CBFβ-SMMHC in Acute Myelogenous Leukemia with inv(16)

Markus, Ján; Garin, Matthew T.; Bies, Juraj; Galili, Naomi; Raza, Azra; Thirman, Michael J.; Beau, Michelle M. Le; Rowley, Janet D.; Liu, P. Paul; Wolff, Linda

doi:10.1158/0008-5472.can-06-2964

Cited by 20 publications

(18 citation statements)

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“…Previously, low RNA levels of p15 were reported in AML (Schwaller et al, 1997) which was also correlated with methylation of this gene (Matsuno et al, 2005). However, Markus et al (2007) reported silencing of p15 gene in AML even in the absence of methylation, suggesting other cellular mechanisms to be involved, but most importantly this pointed to the significance of this gene in the pathology of the AML disease. In this study a methylation frequency of 11% was seen in CML patients.…”

Section: Discussionmentioning

confidence: 95%

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

Bodoor

Haddad

Alkhateeb

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Aberrant DNA methylation of tumor suppressor genes has been reported in all major types of leukemia with potential involvement in the inactivation of regulatory cell cycle and apoptosis genes. However, most of the previous reports did not show the extent of concurrent methylation of multiple genes in the four leukemia types. Here, we analyzed six key genes (p14, p15, p16, p53, DAPK and TMS1) for DNA methylation using methylation specific PCR to analyze peripheral blood of 78 leukemia patients (24 CML, 25 CLL, 12 AML, and 17 ALL) and 24 healthy volunteers. In CML, methylation was detected for p15 (11%), p16 (9%), p53 (23%) and DAPK (23%), in CLL, p14 (25%), p15 (19%), p16 (12%), p53 (17%) and DAPK (36%), in AML, p14 (8%), p15 (45%), p53 (9%) and DAPK (17%) and in ALL, p15 (14%), p16 (8%), and p53 (8%). This study highlighted an essential role of DAPK methylation in chronic leukemia in contrast to p15 methylation in the acute cases, whereas TMS1 hypermethylation was absent in all cases. Furthermore, hypermethylation of multiple genes per patient was observed, with obvious selectiveness in the 9p21 chromosomal region genes (p14, p15 and p16). Interestingly, methylation of p15 increased the risk of methylation in p53, and vice versa, by five folds (p=0.03) indicating possible synergistic epigenetic disruption of different phases of the cell cycle or between the cell cycle and apoptosis. The investigation of multiple relationships between methylated genes might shed light on tumor specific inactivation of the cell cycle and apoptotic pathways.

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Section: Discussionmentioning

confidence: 95%

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

Bodoor

Haddad

Alkhateeb

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…In this type of AML, the inversion (16) results in a fusion protein between the core binding factor (CBFβ) and the smooth myosin heavy chain gene (SMMHC). This chimeric transcription factor CBFβ-SMMHC binds directly to the promoter of p15INK4b and represses its expression (Markus et al, 2007). These results further emphasize an important role of p15INK4b silencing in leukemogenesis of the myeloid lineage, and suggest, that in the absence of a repressive epigenetic event, other mechanisms may result in inhibition of p15INK4b expression (Markus et al, 2007).…”

Section: Introductionmentioning

confidence: 82%

“…In the pediatric form of the disease, juvenile myelomonocytic leukemia (JMML), p15INK4b hypermethylation is found to be a less frequent, however, still significant event (17% of cases) (Hasegawa et al, 2005). With regards to cytogenetic abnormalities, p15INK4b methylation levels have been found to occur at higher frequencies in AML/MDS patients with an unfavorable karyotype (Wong et al, 2000;Galm et al, 2005;Shimamoto et al, 2005;Markus et al, 2007). Cases with unmethylated or low levels of hypermethylated p15INK4b were associated with normal karyotype or with those karyotypic abnormalities that are associated with a favorable prognosis (Wong et al, 2000;Markus et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…With regards to cytogenetic abnormalities, p15INK4b methylation levels have been found to occur at higher frequencies in AML/MDS patients with an unfavorable karyotype (Wong et al, 2000;Galm et al, 2005;Shimamoto et al, 2005;Markus et al, 2007). Cases with unmethylated or low levels of hypermethylated p15INK4b were associated with normal karyotype or with those karyotypic abnormalities that are associated with a favorable prognosis (Wong et al, 2000;Markus et al, 2007). Studies have consistently reported an increased tendency for p15INK4b hypermethylation in unfavorable cytogenetics (Shimamoto et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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p15INK4b, a Tumor Suppressor in Acute Myeloid Leukemia

Fares¹,

Wolff²,

Bies³

2011

Myeloid Leukemia - Basic Mechanisms of Leukemogenesis

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“…A striking 80% of human leukemia and MDS cases have silenced expression of the CDKN2B locus that encodes the tumor suppressor p15Ink4b [2][3][4][5][6][7]. Nonetheless, the function of p15Ink4b in the disease development remains to be elucidated [8,9].…”

Section: Introductionmentioning

confidence: 99%

Brief Report: Loss of p15Ink4b Accelerates Development of Myeloid Neoplasms in Nup98‐HoxD13 Transgenic Mice

et al. 2014

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Homeostasis of hematopoietic stem and progenitor cells is a tightly regulated process. The disturbance of the balance in the hematopoietic progenitor pool can result in favorable conditions for development of diseases such as myelodysplastic syndromes and leukemia. It has been shown recently that mice lacking p15Ink4b have skewed differentiation of common myeloid progenitors toward the myeloid lineage at the expense of erythroid progenitors. The lack of p15INK4B expression in human leukemic blasts has been linked to poor prognosis and increased risk of myelodysplastic syndromes transformation to acute myeloid leukemia. However, the role of p15Ink4b in disease development is just beginning to be elucidated. This study examines the collaboration of the loss of p15Ink4b with Nup98-HoxD13 translocation in the development of hematological malignancies in a mouse model. Here, we report that loss of p15Ink4b collaborates with Nup98-HoxD13 transgene in the development of predominantly myeloid neoplasms, namely acute myeloid leukemia, myeloproliferative disease, and myelodysplastic syndromes. This mouse model could be a very valuable tool for studying p15Ink4b function in tumorigenesis as well as preclinical drug testing.

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Methylation-Independent Silencing of the Tumor Suppressor INK4b (p15) by CBFβ-SMMHC in Acute Myelogenous Leukemia with inv(16)

Cited by 20 publications

References 50 publications

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

p15INK4b, a Tumor Suppressor in Acute Myeloid Leukemia

Brief Report: Loss of p15Ink4b Accelerates Development of Myeloid Neoplasms in Nup98‐HoxD13 Transgenic Mice

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