The cyclin‐dependent kinase inhibitors p18INK4c and p19INK4d are highly expressed in CD34+ progenitor and acute myeloid leukaemic cells but not in normal differentiated myeloid cells

Tschan, Mario P.; Peters, U; Cajot, Jean François; Betticher, Daniel; Fey, Martin F.; Tobler, Andreas

doi:10.1046/j.1365-2141.1999.01617.x

Cited by 21 publications

(12 citation statements)

References 26 publications

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“…30 However, overexpression of CDK4 eliminates all INK4 family members, and p15 INK4b , p18 INK4c , and p16 INK4d can potentially function as tumor-suppressor genes. As confirmation in other studies, [37][38][39] we found that normal human CD34 ϩ cells express p15 INK4b , p18 INK4c , and p19 INK4d , in addition to p16 INK4a . Thus, on this evidence alone, we cannot attribute the effects found in primary hematopoietic progenitor cells specifically to abrogation of p16 INK4a .…”

Section: Discussionsupporting

confidence: 91%

The influence of INK4 proteins on growth and self-renewal kinetics of hematopoietic progenitor cells

Lewis

Chinswangwatanakul

Zheng

et al. 2001

Blood

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This study investigated the influence of expression of proteins of the INK4 family, particularly p16, on the growth and selfrenewal kinetics of hematopoietic cells. First, retrovirus-mediated gene transfer (RMGT) was used to restore p16 INK4a expression in the p16 INK4a -deficient lymphoid and myeloid cell lines BV173 and K562, and it was confirmed that this inhibited their growth. Second, to sequester p16 INK4a and related INK4 proteins, cyclindependent kinase 4 (CDK4) was retrovirally transduced into normal human CD34 ؉ bone marrow cells and then cultured in myeloid colony-forming cell (CFC) assays. The growth of CDK4-transduced colonies was more rapid; the cell-doubling time was reduced; and, upon replating, the colonies produced greater yields of secondary colonies than mock-untransduced controls. Third, colony formation was compared by marrow cells from p16 INK4a؊/؊ mice and wild-type mice. The results from p16 INK4a؊/؊ marrow were similar to those from CDK4-transduced human CFCs, in terms of growth rate and replating ability, and were partially reversed by RMGT of p16 INK4a IntroductionDeletion of the tumor-suppressor gene p16 INK4a has been implicated in tumorigenesis in general 1 and in leukemogenesis in particular. [2][3][4][5] It has been found in 25% to 60% of cases of acute leukemia and 20% to 50% of cases of lymphoma. 6 Although deletion of the p16 INK4a gene is uncommon in acute myeloid leukemia, messenger RNA expression is frequently undetectable, possibly as a result of DNA hypermethylation or mutations in the p16 INK4a promotor region. 7 These observations raise the possibility that p16 INK4a expression plays an important role in the regulation of normal hematopoiesis. There is ample evidence that restoration of p16 INK4a into p16 INK4a -deficient leukemic cell lines reduces their proliferation rate in liquid culture and some evidence that it suppresses their ability to form colonies in semisolid culture, 8,9 but the effects of p16 INK4a expression on primary normal hematopoietic cell proliferation have not been examined. In particular, it is not known whether p16 INK4a has any effects on the kinetics of progenitor cell renewal and differentiation. This is important because transformation of leukemic target cells must be associated with an increase in self-renewal probability above the steady-state value of 0.5 before the leukemic clone can expand, become established, and eventually predominate over normal hematopoiesis. [10][11][12] The p16 INK4a protein is the prototypic member of the INK4 13 This pathway (the pRB pathway) regulates the transition from G 1 to S phase of the cell cycle. The formation of complexes between cyclin D and CDK4 is inhibited by p16 INK4a through binding to CDK4/6. The cyclin D-CDK4/6 complex phosphorylates pRB, resulting in the release of transcription factors so that the genes necessary for cell cycle progression can be transcribed. 14 The pRB family of pocket proteins consists of pRB itself and the structurally related proteins p107 and p130. They are negative ...

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Section: Discussionsupporting

confidence: 91%

The influence of INK4 proteins on growth and self-renewal kinetics of hematopoietic progenitor cells

Lewis

Chinswangwatanakul

Zheng

et al. 2001

Blood

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“…Since mutations of the Ink4c gene are relatively rare in human cancers (Drexler, 1998), the biological characterization of p18/INK4c is not fully conducted compared with other members of the INK4 family. Recent investigations, however, revealed that p18/INK4c is ubiquitously expressed in normal tissues (Thullberg et al, 2000), and also abundant in CD34 + hematopoietic progenitor cells (Tschan et al, 1999). p18/INK4c downregulates along with myeloid differentiation, and became undetectable in mature granulocytes and monocytes (Tschan et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…Recent investigations, however, revealed that p18/INK4c is ubiquitously expressed in normal tissues (Thullberg et al, 2000), and also abundant in CD34 + hematopoietic progenitor cells (Tschan et al, 1999). p18/INK4c downregulates along with myeloid differentiation, and became undetectable in mature granulocytes and monocytes (Tschan et al, 1999). It has been reported that p18/INK4c is a downstream target of interleukin-6, and plays a role in exit from the cell cycle during terminal differentiation of B-lymphocytes (Morse et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Suppression of ARG kinase activity by STI571 induces cell cycle arrest through up-regulation of CDK inhibitor p18/INK4c

et al. 2003

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ARG is a tyrosine kinase closely related to ABL, which is oncogenic when fused to the transcriptional repressor ETV6 (ETS translocation variant 6). In this study, we investigated the growth-inhibitory effect of STI571 (signal transduction inhibitor number 571) on ETV6/ARGexpressing cells and its molecular mechanisms using HT93A, a cell line derived from a patient with AML-M3 carrying t(1;12). STI571 effectively suppressed overall tyrosyl phosphorylation of intracellular proteins including ETV6/ARG fusion protein, as well as the growth of HT93A cells with an IC 50 of 200 nm. The growth inhibition was primarily because of cell cycle arrest at G1 phase when cells were treated with 100 nm STI571 for 48 h, and apoptosis was induced after longer exposure (72 h) or by a higher dose (1000 nm). STI571 increased the amount of p18/INK4c after 2 h of culture, when the cell cycle pattern was not yet affected, but not that of other CDK inhibitors (CKI). p18/INK4c was more abundant in G1-enriched fractions than in S-and G2/Menriched fractions of STI571-treated HT93A cells, suggesting that the upregulation of p18/INK4c expression correlates with the cell cycle arrest. Treatment of HT93A cells with antisense oligonucleotides against the Ink4c gene abrogated the growth inhibition by STI571. These results suggest that leukemogenesis by an aberrant ARG kinase involves the suppression of p18/INK4c, which is ubiquitously expressed and considered the major CKI in hematopoietic stem cells. STI571 can be an effective drug for the treatment of leukemias with deregulated ARG kinase activity.

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“…Interestingly, many studies indicate that tumor-suppressor genes, including PTEN, p53, retinoblastoma (Rb), PML, APC, and FBw7, may play critical roles in maintaining SCs in a quiescent state. p18, a strong inhibitor for stem cell self-renewal has been suggested to be involved in the symmetric division of precursor cells in developing mouse brain (Tschan et al, 1999) and HSC self-renewal Yuan et al, 2004). The absence of p18 causes enhanced stem cell renewal, leading to an increased stem cell pool.…”

Section: Cell Cycle In Normal and Tumor Stem Cellsmentioning

confidence: 99%

Cancer Stem Cells and Their Niche

Gallego¹,

Villaamil²,

Prado³

et al. 2011

Cancer Stem Cells Theories and Practice

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The cyclin‐dependent kinase inhibitors p18^INK4c and p19^INK4d are highly expressed in CD34⁺ progenitor and acute myeloid leukaemic cells but not in normal differentiated myeloid cells

Cited by 21 publications

References 26 publications

The influence of INK4 proteins on growth and self-renewal kinetics of hematopoietic progenitor cells

The influence of INK4 proteins on growth and self-renewal kinetics of hematopoietic progenitor cells

Suppression of ARG kinase activity by STI571 induces cell cycle arrest through up-regulation of CDK inhibitor p18/INK4c

Cancer Stem Cells and Their Niche

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