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Blood, 1 June 2001, Vol. 97, No. 11, pp. 3424-3432
HEMATOPOIESIS
Increased expression of the INK4a/ARF locus in
polycythemia vera
Chunhua Dai and
Sanford B. Krantz
From the Department of Veterans Affairs Medical
Service, Department of Medicine, Division of
Hematology/Oncology; and the Vanderbilt-Ingram Cancer Center,
Vanderbilt University, Nashville, TN.
The retinoblastoma (Rb), cyclin-dependent kinase (CDK), and CDK
inhibitor genes regulate cell generation, and deregulation can produce
increased cell growth and tumorigenesis. Polycythemia vera (PV) is a
clonal myeloproliferative disease where the mechanism producing
increased hematopoiesis is still unknown. To investigate possible
defects in cell-cycle regulation in PV, the expression of Rb and CDK
inhibitor gene messenger RNAs (mRNAs) in highly purified human
erythroid colony-forming cells (ECFCs) was screened using an
RNase protection assay (RPA) and 11 gene probes. It was found that RNA
representing exon 2 of p16INK4a and p14ARF was
enhanced by 2.8- to 15.9-fold in 11 patients with PV. No increase of
exon 2 mRNA was evident in the T cells of patients with PV, or in the
ECFCs and T cells from patients with secondary polycythemia. p27 also
had elevated mRNA expression in PV ECFCs, but to a lesser degree.
Because the INK4a/ARF locus encodes 2 tumor suppressors,
p16INK4a and p14ARF with the same exon 2 sequence, the increased mRNA fragment could represent either one. To
clarify this, mRNA representing the unique first exons of INK4a and ARF
were analyzed by semiquantitative reverse transcription-polymerase
chain reaction. This demonstrated that mRNAs from the first exons of
both genes were increased in erythroid and granulocyte-macrophage cells
and Western blot analysis showed that the INK4a protein
(p16INK4a) was increased in PV ECFCs. Sequencing revealed
no mutations of INK4a or ARF in 10 patients with PV.
p16INK4a is an important negative cell-cycle regulator, but
in contrast with a wide range of malignancies where inactivation of the
INK4a gene is one of the most common carcinogenetic events,
in PV p16 INK4a expression was dramatically increased
without a significant change in ECFC cell cycle compared with normal
ECFCs. It is quite likely that p16INK4a and
p14ARF are not the pathogenetic cause of PV, but instead
represent a cellular response to an abnormality of a downstream
regulator of proliferation such as cyclin D, CDK4/CDK6, Rb, or E2F.
Further work to delineate the function of these genes in PV
is in progress.
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