Human Molecular Genetics, 2000, Vol. 9, No. 15 2297-2304
© 2000 Oxford University Press
RNA hyperediting and alternative splicing of hematopoietic cell phosphatase (PTPN6) gene in acute myeloid leukemia
Department of Biology and Genetics, University of Milan, Medical Faculty, 20133 Milan, Italy and 1Division of Hematology, Niguarda Hospital, 20162 Milan, Italy.
Received 1 June 2000; Revised and Accepted 17 July 2000.
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ABSTRACT |
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The SH2 domain-containing tyrosine phosphatase PTPN6 (SHP-1, PTP1C, HCP) is a 68 kDa cytoplasmic protein primarily expressed in hematopoietic cell development, proliferation and receptor-mediated mitogenic signaling pathways. By means of direct dephosphorylation, it down-regulates a broad spectrum of growth-promoting receptors, including the Kit tyrosine kinase, activated to elicit a prominent cascade of intracellular events by stem cell factor binding. The pivotal contribution of PTPN6 in modulating myeloid cell signaling has been revealed by the finding that shp-1 mutation is responsible for the overexpansion and inappropriate activation of myelomonocytic populations in motheaten (me/me) and motheaten viable (mev/mev) mice. Association of PTPN6 with c-Kit and negative modulation of the myeloid leukocyte signal transduction pathways prompted us to examine the expression of the protein tyrosine phosphatase PTPN6 gene in CD34+/CD117+ blasts from acute myeloid leukemia patients. We identified and cloned cDNAs representing novel PTPN6 mRNA species, derived from aberrant splicing within the N-SH2 domain leading to retention of intron 3. Sequence analysis of cDNA clones revealed multiple A
G editing conversions. The editing of PTPN6 mRNA mainly occurred as an AG conversion of A7866, which represents the putative branch site in IVS3 of PTPN6 mRNA. Evidence that editing of A7866 abrogates splicing has been obtained in vitro by using an edited clone and its backward clone generated by site-directed mutagenesis. The level of the aberrant intron-retaining splice variant, evaluated by semi-quantitative RT–PCR, was lower in CD117+-AML bone marrow mononuclear cells at remission than at diagnosis, suggesting the involvement of post-transcriptional PTPN6 processing in leukemogenesis. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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RNA editing is a post-transcriptional pre-mRNA base modification of which four different classes have been observed in mammalian cells. Of particular interest for the study herein reported is the deamination of adenosine to form inosine, that interacts with ribosomes in the same way as guanine, being detected by reverse transcription as an A
G transition (1). This type of editing has been described in mRNA encoding receptor subunits of glutamate-gated ion channels (GluR-B) which mediate fast excitatory neurotransmissions (2,3). Tumor suppressor genes such as NF1 (4) and WT1 (5) have also been identified as targets of mRNA editing. In NF1 mRNA, the editing site involves C3916 in exon 23-1, which by change to U introduces an in-frame stop codon (4). A potential role in NF1 tumorigenesis has been suggested by the authors based on the correlation between CU RNA editing levels and tumor progression. The UC839 conversion of WT1 cDNA has been proposed to play a role in the developmental stage-specific functions of the WT1 protein (5).
By addressing an expression analysis of the protein tyrosine phosphatase PTPN6 (SHP-1, PTP1C, HCPH) gene on CD34+/CD117+(C-KIT+) blasts, we have identified and cloned cDNAs representing novel PTPN6 mRNA species derived from editing and aberrant splicing. Editing of PTPN6 mRNA mainly occurred as an AG conversion of adenosine 7866, which represents the putative branch site in IVS3 of PTPN6 mRNA.
The SH2 domain-containing tyrosine phosphatase PTPN6 is a 68 kDa cytoplasmic protein primarily expressed in hematopoietic cell development (6,7), proliferation and receptor-mediated mitogenic signaling pathways (8–12). The role of PTPN6 in hematopoiesis has been shown in motheaten mice with mutations at the shp-1 (Hcph) locus. Splicing mutations affecting either the SH2 or PTPase domain of SHP-1 in motheaten (me) and viable motheaten (mev) mice lead to multiple hematopoietic abnormalities, including the overexpansion and accumulation of myelomonocytic populations (13–15). SHP-1 mRNA from me bone marrow cells have a 101 bp frameshift deletion in the coding region of the N-terminal SH2 domain, whereas those from mev bone marrow have either a 15 bp in-frame deletion or a 69 bp in-frame insertion within the PTPase catalytic domain (15,16). These abnormalities result in a severe impairment of the expression and of the catalytic activity of SHP-1, strongly suggesting that the motheaten phenotype is caused by loss-of-function mutations in the shp-1 gene (13). PTPN6 appears to exert primarily inhibitory effects on the signaling cascades in which it participates. By means of direct dephosphorylation, it down-regulates a broad spectrum of growth-promoting receptors, including receptor tyrosine kinases such as c-Kit (17,18), and CSF-1 (9). By dephosphorylation of the associated Janus family tyrosine kinase 2 (JAK2), PTPN6 also modulates cytokine receptors such as IL-3 (8) and erythropoietin (19,20). These data identify this protein tyrosine phosphatase as a critical player in the modulation of hematopoietic cells growth and function (12).
Signaling events induced by c-Kit binding with its ligand, stem cell factor (SCF), involve the association of the activated receptor with phosphatidylinositol 3-kinase (21,22), phospholipase C
-1 (23,24), megakaryocyte-associated tyrosine kinase (MATK) (25) and a number of other cytosolic signaling effectors, including PTPN6 (17,18). On the basis of the emerging evidence that SHP-1 inhibits proliferative signals evoked by c-Kit receptor in response to its ligand in bone marrow progenitor cells (26,27) and that c-Kit-activating mutations lead to the development of acute myeloid leukemia (28–31) also by inducing SHP-1 degradation (32), we investigated by RT–PCR the expression of PTPN6 in CD34+/CD117+(KIT+) acute myeloid leukemia patients. We detected an as yet undescribed PTPN6 mRNA species found to retain the entire IVS3 of the PTPN6 gene at levels significantly increased compared with normal bone marrow and the expressing human myeloid leukemia cell line HL-60 (6). This finding prompted us to explore in detail the mechanism generating the novel transcripts by a complementary set of approaches, involving poisoned primer extension and in vitro splicing. Interestingly, the level of the aberrant intron-retaining splice variant was found to be lower in CD117+-AML bone marrow mononuclear cells (BMMNCs) at remission, thus suggesting the involvement of post-transcriptional PTPN6 processing in leukemogenesis.
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RESULTS |
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RT–PCR analysis of the PTPN6 gene and characterization of the splice variant retaining IVS3
PTPN6 expression analysis on BM blasts from AML patients was performed by RT–PCR using two overlapping sets of primers, designed on the basis of published cDNA sequence (33), which amplify the portion of PTPN6 mRNA encoding either the SH2 or the phosphatase domain (Fig. 1a).
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Using the PTP-141 and PTP-897 primers that amplify the SH2 domains, we found two products on BMMNCs from leukemic patients: one of the expected size of 757 bp and a second of
1000 bp. The results of agarose gel electrophoresis of cDNA transcripts from the BMMNCs and peripheral blood mononuclear cells (PBMNCs) of patient AML-34, the bone marrow of a healthy donor and the HL-60 cell line are shown in Figure 1b. Although less abundant, the abnormal fragment is also present in the normal bone marrow and in HL-60 cells and appears to be 250 bp longer than the expected transcript. Direct sequence analysis revealed that the cDNA fragment containing the extra 251 bp represents the entire IVS3 located between nucleotides 275 and 276 of the c-DNA sequence (Fig. 1a) according to NCBI (accession no. NM_002831).
Cloning of the splice variant points to editing modifications
In order to envisage the nature of the abnormal PTPN6 transcript found in leukemic BMMNCs (and at lower levels in normal bone marrow and HL-60 cells), we cloned the gel-excised 1008 bp intron-retaining fragment from patient AML-34. Sequence analysis of a number of isolated clones revealed multiple AG editing conversions with somewhat different patterns (Fig. 2). Of particular interest is the AG conversion located 27 nucleotides upstream of the 3'-splice acceptor site, because this represents the putative branch site of IVS3 (Fig. 1a).
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). A potential 44 amino acid protein is terminated by a UAG stop codon (asterisked) arising from the retention of intron 3 in the edited cDNA clones. A pair of in-frame potential translation reinitiation codons downstream of the premature stop codon are indicated in bold.Genomic DNA from bone marrow of patient AML-34 at diagnosis was sequenced by primer PTP2a, located in IVS2, and primer PTP3b, located in IVS4, from nucleotide 7449 to 8150 (according to NCBI accession no. X82818), giving a total sequence of 702 nucleotides which includes the target IVS3. No sequence abnormality was detected throughout, including IVS3 and its flanking regions containing the acceptor and donor splice junctions (data not shown).
Semi-quantitative RT–PCR of PTPN6 transcripts from leukemic BMMNCs at diagnosis and remission
With the aim of evaluating the extent of the expression of the incorrectly spliced PTPN6 mRNA, we performed a semi-quantitative RT–PCR on bone marrow blasts from seven CD117+/CD34+ acute myeloid leukemia patients at diagnosis and remission, as well as on bone marrow of healthy donors and HL-60 cells. For this purpose, we used the PTP-141-FAM and PTP-346 primers which narrow down the region involved in the alternative splicing and produce the expected 206 bp fragment and the alternative spliced fragment of 457 bp (Fig. 3a). Following the capillary electrophoresis of the RT–PCR products using an ABI 310 genetic analyzer, we could obtain peak profiles representing the quantitative measurements of each sample (Fig. 3a). The relative percentages of the alternative transcript in all of the investigated cases can be seen in Figure 3b, which shows that the levels of the abnormally spliced transcript were significantly higher in the BMMNCs at diagnosis than at remission. Patient AML-17, who shows a less significant drop of the abnormal transcript at the follow-up, was indeed re-evaluated at a phase of partial remission (see Materials and Methods). On an average, the lower levels of the abnormal transcript at remission were higher than the levels in the controls.
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Poisoned primer extension assay for RNA editing
In order to investigate whether the mRNA editing at the putative branch site plays a role in the intron retention of PTPN6 mRNA, we performed poisoned primer extension assays involving the gel-isolation of the aberrant transcripts in each sample and the quantification of their products (Fig. 4a; see Materials and Methods). Each lane of the autoradiograph (Fig. 4b) shows three major bands corresponding to the primer, the first stop primer-extension product arising from unedited adenosine and the second stop primer-extension product arising from edited cDNA. High levels of this specific editing modification (ranging from 38 to 61%) affect the adenine located 27 bp upstream of the intron 3–exon 4 junction of the intron-containing transcript (data not shown). Figure 4c shows a representative poisoned primer extension autoradiograph of cDNA clones D2.5 (containing the normal adenine) and E4.18 (containing the guanosine resulting from the editing in the same position).
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In vitro splicing of the A7866
G edited cloneTheoretical evidence that A7866 may act as a branch site is provided by the perfectly full coincidence of its neighboring nucleotides with the branch site consensus sequence and that of the ß-globin intron I branch site (Fig. 5a). In order to obtain experimental evidence that A7866 is directly responsible for the alternative splicing of PTPN6 mRNA and represents the branch point, we performed in vitro splicing reaction experiments on clones E4.18 (containing the A7866
G editing as the only conversion) and D2.5 (which lacks this modification). Clone D2.5 was obtained by means of site-directed mutagenesis on the edited E4.18 clone which induced it to revert to the normal state. The substrates for in vitro splicing were prepared by means of the in vitro transcription of the SP6 vector promoter and the addition of a 5'-cap structure analog. Figure 5b shows the RT–PCR analysis after the splicing assay (see Materials and Methods), which reveals the normal 206 bp splice product [which was also confirmed by sequence analysis (data not shown)] for clone D2.5 (lane +) and the absence of splicing activity for the AG edited E4.18 clone (lane +). This finding confirms that the editing conversion abolishes splicing by destroying the adenine branch formation site without activating any cryptic 3' splice site.
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DISCUSSION |
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Extensive double stranded RNA editing that eliminates a 3' splice acceptor site and leads to the generation of an alternative transcript retaining intron 4 has been described in the case of the Drosophila 4f-rnp gene (34). Our results are the first documenting aberrant splicing within the N-terminal SH2 domain of the PTPN6 gene, arising from double stranded RNA-specific adenosine deamination of the IVS3 branch site A7866 and leading to a novel PTPN6 transcript retaining intron 3. It is predicted that the retention of the 251 bp intron 3 leads to a nonsense translation of PTPN6 mRNA, which may lead to the production of a non-functional protein and could activate translation reinitiation at the in-frame ATG of IVS3. Translation reinitiation is proposed to abrogate nonsense-mediated mRNA decay accounting for the relative stability of the IVS3-containing PTPN6 transcript (35). Data obtained on apoB and NF1 pointed to a defect in editing regulation rather than an increase in deaminase activity leading to the proposal of gene-specific factors involvement in RNA editing (4,36). Nevertheless the accumulation of edited sequences by a defect in the degradation of mis-spliced pre-mRNA is an alternative hypothesis that cannot be ignored. The destabilizing effect of the introduced nonsense mutation has been shown to be greater when it occurs close to the 5'-end of mRNA (37), as is the case for the stop codon introduced by intron retention into PTPN6 mRNA. Furthermore, a downstream instability element consisting of a pair of in-frame initiation codons (38) (Fig. 2) may contribute towards the decrease in PTPN6 levels. It is also worth noting that several adenine residues located in the coding PTPN6 sequence were detected by clone sequencing, to be a target for mRNA editing (Fig. 2). All of the identified changes are predicted to be missense alterations, of which potential consequences on the protein function appear more complex than the loss of function predicted by the splicing alteration elucidated here.
There is evidence that PTPN6 binds partner proteins through its N-terminal SH2 domain (as it does with the Kit receptor) (17) and through the same domain self-inhibits phosphatase activity (39). The disruption of the N-terminal SH2 domain leads to a constitutively activated enzyme that is incapable of binding the tyrosine residues of partner proteins (40) and it is known that SHP-1 directly dephosphorylates and negatively regulates c-Kit (18,26,27). Furthermore, it has been found that the murine c-kit mutation at codon 814, corresponding to human 816 observed in core-binding factor leukemias (29), leads to the degradation of SHP-1 through the ubiquitin-dependent proteolytic pathway (32). The importance of SHP1 c-kit binding is underlined by data showing that deletion of Tyr569, identified as the SHP-1 binding site on c-kit (18), substantially enhances the mitogenic and transforming properties of the feline c-kit receptor. This deletion represents one of the mutations of the v-kit oncogene (41). It has also been suggested that the loss of SHP-1 activity caused by the me mutation increases Kit signaling and leads to increased cell survival (26).
Taken together, these findings indicate that PTPN6 may play a tumor-suppressing role not only because PTPN6 alters c-Kit activity but also because PTPN6 mutations may have oncogenic potential, as has been shown by the increased frequency of lymphoma in mice that are heterozygous for the me or mev mutation (14,18). The loss of the inhibition of c-Kit signaling by PTPN6 may thus represent a significant molecular event in terms of hematopoietic transformation.
The potential role of NF1 mRNA editing in tumorigenesis has already been described (4). It is also interesting to note that recent studies have reported that p53 (42), p27 (43) and Nf1 haplo-insufficiency (44) may confer a growth advantage by means of pathways that do not require the inactivation of the normal allele.
The current data concerning PTPN6 functions identify it as a critical player in the modulation of hematopoietic cell growth and function (8–12). An increase in the mRNA editing rate in acute myeloid leukemia may cause a functional haplo-insufficiency of PTPN6 that disregulates its suppressor function on c-Kit signaling.
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MATERIALS AND METHODS |
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Patient samples
Bone marrow and peripheral blood samples were obtained after informed consent from two healthy donors (BM-MI4238 and BM-MI1032) and seven acute myeloid leukemia patients at diagnosis, corresponding to the acute phase of disease, and characterized by CD34 and CD117 (c-kit) positivity. We also analyzed follow-up samples represented by peripheral blood stem cells (PBSCs) at first complete remission (leukopheresis after chemotherapy and G-CSF treatment) for patients AML-7, AML-23 and AML-32, PBSCs at partial remission (leukopheresis after chemotherapy and G-CSF treatment) for patient AML-17 and bone marrow harvest for autologous bone marrow transplantation at first complete remission for patient AML-21.
RT–PCR assay and sequencing
Total RNA was extracted from the BMMNCs and PBMNCs and the mobilized PBSCs of the follow-up samples using TRIzol (Life Technologies, Rockville, MD) according to the manufacturer’s protocol. We generated first-strand cDNA using total RNA (1.5 µg), enhanced avian reverse transcriptase (AMV-RT; 1 U; Sigma, St Louis, MO), random nonamers (Sigma) and Rnase inhibitor (0.5 U; Sigma) in a 20 µl reaction volume. PCR reaction was performed using primers PTP-141 (5'-CAGGATGGTGAGGTGGTTTC-3'), spanning the exon 2–exon 3 boundary, and PTP-897 (5'-CAAACTCTCAAACTCCTCCCA-3'), spanning the exon 7–exon 8 boundary. The PCR conditions were as follows: one cycle of 95°C for 3 min, 55°C for 1 min, 72°C for 1 min, followed by 30 cycles of 95°C for 30 s, 55°C for 30 s, 72°C for 40 s and a final extension of 7 min at 72°C. All of the PCR products were purified using the QIAquick PCR purification kit (Qiagen, Hilden, Germany) and sequenced using the ABI Prism Big Dye Terminator Cycle Sequencing Ready Reaction (Applied Biosystems, Foster City, CA) by ABI Prism 310 sequence analyzer (Applied Biosystems). The 1008 bp cDNA fragment was sequenced using the PTP-141 and PTP-897 primers. Sequencing of genomic DNA was performed using primers PTP2a, located in IVS2, and PTP3b, located in IVS4; the critical 142 bp genomic fragment, which includes the target IVS3, was also sequenced using the PTP-205 and PTP-346 primers (genomic primer sequences are available on request).
To evaluate the range of aberrant spliced PTPN6 transcripts an RT–PCR using PTP-141-FAM and PTP-346 primers was performed. The PCR conditions were as follows: one cycle of 95°C for 3 min, 59°C for 1 min, 72°C for 1 min, followed by 30 cycles of 95°C for 25 s, 59°C for 30 s, 72°C for 35 s. Quantitative measurements were obtained after capillary electrophoresis of RT–PCR products using an ABI 310 genetic analyzer and Gene Scan software (Applied Biosystems) for each sample.
In order to evaluate the amplification efficiency of normal 206 bp and alternatively spliced 457 bp fragments, a PCR assay was performed and samples were analyzed at different amplification cycles. Amplification efficiency was identical for the two templates during the whole process (data not shown). Therefore, the different intensity of the bands of the 206 and 457 bp transcripts is considered to reflect their relative expression levels.
cDNA cloning and site-directed mutagenesis
The RT–PCR 1008 bp intron-retaining fragment from patient AML-34 amplified using PTP-141 and PTP-897 primers was cloned into the pGEM-T Easy Vector (Promega, Madison, WI). DNA sequencing was performed on both strands using the ABI Prism Big Dye Terminator Cycle Sequencing Ready Reaction by ABI Prism 310 sequence analyzer. E4.18 clone (containing the A7866G editing as the only conversion) was mutated in order to revert the guanosine to the normal adenine (clone D2.5) by oligonucleotide-directed site mutagenesis, using the QuikChange Site-Directed Mutagenesis kit (Stratagene, La Jolla, CA).
Poisoned primer extension
The 457 bp amplified fragment was purified from residual nucleotides by means of electrophoresis on 1.8% agarose gel, denatured in water at 95°C for 5 min. and cooled on ice. The denatured fragment was mixed with the end-labeled primer [33P]5'-CCTCCTGCCTCTACTCCTGCA-3' for IVS3 of PTPN6 in the presence of 0.1 mM each of dCTP, dGTP and dTTP, and 1 mM of 2'3'ddATP. The reaction products were resolved under denaturing conditions on 6% acrylamide gels containing 7 M urea, and visualized autoradiographically. The gel was then exposed to a phosphor-imager storage screen and the radioactivity in each gel band quantified by means of phosphor-imager scanning (GS-700 Imaging densitometer; Bio-Rad, Richmond, CA). Once the image is scanned, a rectangular box is drawn around a representative band and then replicated a sufficient number of times to provide boxes for each gel band, plus one designed to quantify the background. After subtracting the background counts for each value, the percentage of PTPN6-IVS3 edited mRNA alternatively spliced using the putative branch-site was calculated for each sample. The amount of radioactivity in the band corresponding to the edited species is divided by the total amount of radioactivity in the bands resulting from both the edited and unedited extension products of each assay.
In vitro splicing reaction
SP6/PTPN6 transcripts were synthesized from D2.5 and E4.18 clones with RiboMAX Large Scale RNA Production System (Promega) reagents. A 5' capping of the transcripts was performed according to RNA Splicing System (Promega) protocol. After gel purification of the uniformly 32P-labeled transcripts, an in vitro splicing reaction was performed using 2 ng of gel-purified RNA according to the RNA Splicing System protocol. After further incubation at 30°C for 30 min with HelaSplice Nuclear extract (Promega), the proteins were removed by extraction with an equal volume of phenol:chloroform:isoamyl alcohol (25:24:1). The analysis of processing products was performed by RT–PCR using PTP-141 and PTP-346 primers as previously described. RT–PCR products were resolved on 1.8% agarose gel.
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ACKNOWLEDGEMENTS |
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We thank Drs L. Pezzetti and L. Intropido (Niguarda Hospital, Milan, Italy) for assistance with the sample collection. This work was supported by grants ex-MURST 60% (1999–2000 to L.L.) and ex-MURST 40% (1998–1999 to L.L.)
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +39 02 23693226; Fax: +39 02 70602472; Email: lidia.larizza@unimi.it
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REFERENCES |
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