Lineage‐specific regulation of cell cycle control gene expression during haematopoietic cell differentiation

Abstract

Summary. To maintain the fidelity and integrity of blood formation, the cell cycle is under strict regulation during haematopoietic cell differentiation. To elucidate the molecular mechanisms of cell cycle regulation during haematopoiesis, we examined cell cycle control gene expression during lineage-specific differentiation from CD34 1 progenitor cells. Expression of cyclin-dependent kinases (cdks) and cyclins, except cdk4, was generally suppressed in CD34 1 cells freshly isolated from the bone marrow of healthy volunteers. Among four major cdk inhibitors, p16 was expressed more highly in CD341 cells than in CD34-negative bone marrow mononuclear cells, whereas the amounts of p21 and p27 transcripts increased in the CD34 2 population. The behaviour of cell cycle control genes during haematopoietic differentiation was classified into four patterns: (i) universal upregulation (cdc2, cdk2, cyclin A, cyclin B and p21); (ii) upregulation in specific lineages (cyclin D1, cyclin D3 and p15); (iii) no induction or stable expression (cdk4, cyclin D2, cyclin E and p27); and (iv) universal downregulation (p16). Lineage-specific changes included the sustained elevation of cdc2 and cyclin A during erythroid differentiation, cyclin D1 and p15 induction in myeloid lineage and selective upregulation of cyclin D3 in megakaryocytes. Blocking induction of cyclin D3 resulted in the inhibition of megakaryocytic differentiation. These results suggest that the expression of cell cycle control genes is distinctively regulated in a lineage-dependent manner, reflecting the cell cycle characteristics of each lineage. Some of these genes play an essential role in the process of differentiation itself.

Cell cycle regulators and hematopoiesis

“…Interestingly, although p21 appeared to serve as a nonredundant checkpoint inhibiting stem cell cycling, p21 is highly expressed in replicating hematopoietic progenitor and precursor cells (Furukawa et al, 2000;Steinman et al, 1998;Taniguchi et al, 1999;Yaroslavskiy et al, 1999). The uncoupling of p21 from growth arrest in these cells could result from p21 sequestration away from cdk2 or binding of additional proteins which sustain the activity of p21-cdk complexes (Cheng et al, 1999;Estanyol et al, 1999).…”

Enforced expression of cyclin D2 enhances the proliferative potential of myeloid progenitors, accelerates in vivo myeloid reconstitution, and promotes rescue of mice from lethal myeloablation

“…19 Cyclin D2 and D3 are known to be expressed in normal lymphocytes and all 3 types of D-cyclins in myeloid progenitors. 20,21 D-type cyclins, when overexpressed in the cytokine-dependent 32Dcl3 myeloid progenitor cell line, shorten G1. 22,23 However, whether this can be translated into enhanced proliferative activity of primary hematopoietic progenitor and stem cells has not been investigated.…”

Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia

“…5 Restricted to the myeloid lineage of cells, p15 expression is undetectable in CD34 + progenitor cells, but strongly upregulated by autocrine production of TGF-b during terminal differentiation of granulocytes. [6][7][8][9][10] The p16 gene, on the other hand, is highly expressed in CD34 + progenitor cells, but downregulated during terminal myeloid differentiation. 9 Inactivation of the p14, p15, or p16 genes by homozygous deletion, point mutation or by hypermethylation of the CpG sites at the promoter region has been observed in different neoplasias.…”

“…[6][7][8][9][10] The p16 gene, on the other hand, is highly expressed in CD34 + progenitor cells, but downregulated during terminal myeloid differentiation. 9 Inactivation of the p14, p15, or p16 genes by homozygous deletion, point mutation or by hypermethylation of the CpG sites at the promoter region has been observed in different neoplasias. Whereas point mutations are very rare in hematopoietic malignancies, disruption of the three genes by homozygous deletion, or silencing of p15 and p16 by promoter hypermethylation, are common in lymphoid malignancies as acute lymphoblastic leukemias and multiple myeloma.…”