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The Journal of Immunology, 2001, 167: 1867-1870.
Copyright © 2001 by The American Association of Immunologists

Cutting Edge

Cutting Edge: Predominant Expression of a Novel Ikaros Isoform in Normal Human Hemopoiesis1

Kimberly J. Payne2,*, Jan-Holly Nicolas{dagger}, Judy Y. Zhu*, Lora W. Barsky* and Gay M. Crooks*

* Division of Research Immunology/Bone Marrow Transplantation, Childrens Hospital, Los Angeles, CA 90027; and {dagger} Department of Chemistry and Biochemistry, La Sierra University, Riverside, CA 92515


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Murine studies implicate Ikaros proteins as regulators of hemopoiesis, particularly in the lymphoid lineages. High homology between murine and human Ikaros suggests that Ikaros expression in the two might be similar. However, initial human studies that focused on leukemia detected novel Ikaros transcripts in patient samples. Thus, novel Ikaros splice forms and DNA nonbinding isoforms were linked with malignancy. We undertook an extensive analysis of normal human Ikaros expression to determine whether novel mRNAs are expressed as proteins and the extent to which these splice variants are unique to leukemia. Here we show that both mRNA and protein for DNA nonbinding Ikaros isoforms and splice variants previously linked to leukemia are expressed in normal human cells. However, our studies identify a new Ikaros isoform not previously described in mouse or human. This isoform is the predominant Ikaros protein in normal human cells, but not in leukemia cell lines.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
A variety of studies demonstrate that proteins encoded by the Ikaros gene are required for normal hemopoietic differentiation and proliferation, particularly in the lymphoid lineages (for a review, see Ref. 1 .) The murine Ikaros gene was originally reported to contain 7 exons that are alternately spliced to produce at least 10 isoforms (Fig. 1GoA). (2, 3, 4, 5). Alternate use of exons 3, 4, and 5 results in Ikaros isoforms with zero to four N-terminal zinc fingers (Fig. 1GoA). Longer isoforms with three or four N-terminal zinc fingers (Ikaros isoforms (Ik) 1 through 3)3 bind DNA, whereas those with fewer than three (Ik4 through Ik8) are nonbinding (4, 6). Ikaros isoforms interact to form homo- and heterodimers through two zinc fingers in a common C-terminal domain encoded by exon 7 (3, 6, 7). Shorter, DNA nonbinding isoforms exert a dominant negative effect, inhibiting the ability of longer heterodimer partners to bind DNA (6).



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  		FIGURE 1. Ikaros isoforms and placement of PCR primers. A, Alternate splicing of exons 1–7 of the Ikaros gene gives rise to isoforms Ik1 through Ik8. Zinc fingers are represented as vertical bars. Variants of isoforms with the 30-base deletion (-, with the 60-base insertion (+) or with both (+/-) that have been detected here or elsewhere (9 10 11 14 ) are indicated at right. B, "Deletion primers" designed to amplify Ik1, Ik3, Ik5, and variants of these isoforms with the 30-base deletion in exon 6. C, A previously unidentified Ikaros isoform (Ikx) based on sequence of RT-PCR products (Figs. 2Go and 3Go). D, "Insertion primers" designed to detect Ik1, Ik2, Ik4, Ik7, Ik8, and variants of these isoforms with the 60-base insert following exon 2.

 
Ikaros is highly conserved between mouse and human. Isoforms corresponding to mouse Ik1 through Ik6 were identified in an early study of human cells (8). This suggested that RNA splice patterns were identical in mice and humans; however, subsequent human studies detected transcripts for a number of previously unreported Ikaros splice variants in leukemia samples. A variant of Ik2 with a 60 base insertion following exon 2 was reported (9, 10). Transcripts for several Ikaros isoforms with a 30 base deletion arising from the use of an alternate splice site between exon 6 and exon 7 were also detected (9, 10, 11). The expression of splice variants with insertions or deletions, along with unexpectedly high levels of the shorter, DNA nonbinding Ikaros isoforms were initially linked to leukemia (9, 10, 11, 12).

A recent study detected the 30-base deletion in transcripts present in normal human bone marrow and thymus (13), although the particular isoforms containing the deletion were not determined. In addition, there is now a report of transcripts for Ik1, Ik2, and Ik4 with the 60-base insertion in normal human peripheral blood (14). The expression of Ikaros proteins generated from transcripts with the insertion or deletion has not been reported.

Most human studies to date have focused on Ikaros expression in leukemia samples, and analysis of Ikaros splice variants and expression patterns in normal human hemopoietic tissues, particularly at the protein level, has just begun. Here we describe an extensive analysis of Ikaros mRNA and protein expression in normal human hemopoietic cells.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Cell sources and preparation

Umbilical cord blood and bone marrow were collected according to guidelines approved by the Childrens Hospital Los Angeles Committee on Clinical Investigation (Investigational Review Board), and mononuclear cells were obtained as previously described (15). The T cell acute lymphocytic leukemia (ALL) cell lines Molt-3 and Jurkat E6-1 were obtained from American Type Tissue Culture Collection (Manassas, VA), and the B cell ALL cell line Nalm-6 was provided by Dr. Dario Campana, St. Jude Children’s Research Hospital (Memphis, TN).

RNA extraction and cDNA preparation

Total RNA was obtained using STAT 60 (Teltest, Friendswood, TX) as per manufacturer’s directions. Cytoplasmic RNA fractions were isolated by resuspending washed cells in an ice cold mixture of 48 µl nuclear extraction buffer (10 mM Tris-HCl (pH 7.4), 10 mM NaCl, 3 mM MgCl2, and 0.5% polyoxyethylene isooctylphenyl ether (Sigma, St. Louis, MO) in diethyl pyrocarbonate-treated water and 2 µl RNA guard (Pharmacia Biotech, Uppsala, Sweden)), vortexing for 10 s, incubating for 5 min on ice, and centrifuging at 4°C for 5 min at 1200 rpm to pellet nuclei. Cytosolic fraction (supernatant) was transferred to a separate tube containing 1 ml RNA Stat 60, and RNA extraction was completed as per manufacturer’s directions.

cDNA was prepared using oligo(dT) primers (Pharmacia Biotech) and either the Omniscript kit (Qiagen, Valencia CA) or the Superscript II kit (Life Technologies, Gaithersburg, MD) as per manufacturer’s directions. Equivalent template for RT-PCR analysis of primary cells and cell lines was achieved by normalizing concentrations of RNA or cDNA obtained from similar cell numbers.

RT-PCR analysis

cDNA was subjected to PCR using HotStarTaq (Qiagen) as per manufacturer’s directions. Insertion primers for amplification of Ikaros cDNAs were: forward, 5'-TGAGCCCATGCCGATCCCCGAG-3'; and reverse, 5'-GGTCTTCTGCCATTTCACTGTGATTA-3'. PCR conditions for insertion primers were: a 15-min 95°C hot start followed by 35 cycles of 1 min at 95°C, 1 min at 60°C, 3 min at 72°C; a final 10-min 72°C extension; and cooling to 4°C. Deletion primers for amplification of Ikaros cDNAs were: forward, 5'-GAAGAGAATGGGCGTGCCTGTGAA-3'; and reverse, 5'-CTTCATCATTTCGTTCTCCTTCTCG-3'. PCR conditions for deletion primers were: a 15-min 95°C hot start followed by 10 cycles of 1 min at 95°C, 1 min at 62°C, 3 min at 72°C; 25 cycles of 1 min at 95°C, 1 min at 60°C, 3 min at 72°C; a final 10-min 72°C extension; and cooling to 4°C.

Sequencing of RT-PCR products

Individual bands were cut from gel and subjected to PCR using original primers (either deletion or insertion), and products generating a single band identical in size with that cut from the original gel were sequenced. Sequencing was performed by the Core Facility at the Center for Molecular Biology and Gene Therapy, Loma Linda University (Loma Linda, CA). Isoforms were identified by comparing the sequence of RT-PCR products with that for full length Ik1 cDNA from normal human bone marrow (GenBank accession no. U40462) (16) and previously identified Ikaros splice patterns (3, 8, 9, 10, 11).

Immunoblots

For preparation of cell lysates, washed cells were resuspended in cold universal immunoprecipitation buffer (50 mM Tris, 150 mM NaCl, 2 mM EDTA, 2 mM EGTA, 25 mM NaF, 25 mM {beta}-glycerol phosphate in water) brought up to 1 mM PMSF, 1 µg/ml leupeptin, and 1 µg/ml aprotinin immediately before use. Suspended cells were sonicated on ice for ~10 s, checked for complete lysis by microscope, and then centrifuged at 14,000 rpm for 10 min at 4°C to pellet membranes. Supernatants were diluted in NuPage sample buffer (Invitrogen, Carlsbad, CA) and stored at -80°C. Lysates were run along with Seeblue molecular mass markers on a NuPage 10% Bis-Tris gel with MOPS buffer using the XCell SureLock System (Invitrogen) and transferred to Immobilon-P membrane (Millipore, Bedford, MA) using the Xcell II Blot Module (Invitrogen), all performed as per manufacturer’s instructions.

Ikaros was detected using anti-Ik N-terminal sequence (NTS) and anti-Ik C-terminal sequence (CTS) (polyclonal rabbit Abs specific to the N and C termini, respectively, of all Ikaros isoforms), anti-IkH (polyclonal rabbit Ab specific to residues encoded by the 60-base insert following Ikaros exon 2), or the mouse mAb 2A9 (specific to exon 3 of the Ikaros protein) (generous gifts kindly provided by the laboratory of Dr. S. Smale (Howard Hughes Medical Institute, University of California School of Medicine, Los Angeles CA)); or the commercially available Abs Ikaros M20 and Ikaros E20 (polyclonal goat Abs specific to the N and C termini, respectively, common to all Ikaros isoforms (Santa Cruz Biotechnology, Santa Cruz, CA)). Blots were developed using the ECL+Plus Western blotting detection system and accompanying Abs (Amersham, Arlington, Heights, IL) or anti-goat HRP (Santa Cruz Biotechnology) as per manufacturer’s protocol with the exception that blocking reagent was present continually during Ab incubation.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Normal human hemopoietic cells express transcripts for deletion forms of Ikaros and a previously unidentified Ikaros isoform

DNA sequencing of RT-PCR products from deletion primers (designed to detect Ikaros isoforms with the 30-base deletion in exon 6; Fig. 1GoB) showed that transcripts for Ik1 and a form of Ik1 with the 30-base deletion (Ik1-) were present in normal human cord blood and bone marrow and in three ALL cell lines (Fig. 2Go). The deletion was identical with that found in Ik2, Ik4, Ik7, and Ik8 RT-PCR products generated from ALL patient samples (9, 10, 11).



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  		FIGURE 2. Deletion primers detect a previously unidentified Ikaros isoform and Ikaros deletion forms in normal and leukemia samples. RT-PCR analysis of total cell extracts using "deletion primers" (see Fig. 1GoB). The previously unidentified Ikaros isoform is designated Ikx (see Fig. 1GoC). Variants with the 30-base deletion are designated as deletion forms (Ik1-, Ikx-). Expected lengths of PCR products are shown in parentheses. Ctrl., Control.

 
DNA sequence for the lower pair of bands generated by deletion primers (designated Ikx and Ikx-; Fig. 2Go) was obtained and compared with human Ik1 cDNA sequence (16) and previously reported Ikaros splice patterns (3, 4). Ikx matched the reported Ikaros sequence and used known Ikaros splice sites but was generated from an exon combination previously unreported in mice or humans (Fig. 1GoC). This product was identical with the previously identified Ik3, except that it included exon 6. Ikx- was a form of Ikx with the same 30-base deletion seen in Ik1- (Fig. 2Go).

Transcripts for DNA-binding and nonbinding Ikaros isoforms containing the 60-base insert are present in normal cord blood and bone marrow

RT-PCR using insertion primers (designed to detect Ikaros isoforms with the 60-base insertion following exon 2; Fig. 1GoD) was performed on cytosolic extracts to ensure that RT-PCR products representing insertion forms were not generated from partially processed Ikaros mRNA present in the nucleus.

DNA sequencing of RT-PCR products from insertion primers identified transcripts for the DNA-binding isoforms Ik1, Ikx, and Ik2 as well as the DNA nonbinding isoform Ik4 (Fig. 3Go) in both normal and leukemia samples. In addition, faint bands identified by sequencing as the dominant negative isoforms Ik7 and Ik8 were present in normal cord blood and bone marrow and in some leukemia samples (Fig. 3Go).



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  		FIGURE 3. Ikaros splice forms with a 60-base insertion are present in normal and leukemia samples. RT-PCR analysis of cytoplasmic extracts from indicated cell types using insertion primers (see Fig. 1GoD). The previously unidentified Ikaros isoform is designated Ikx (see Fig. 1GoC). Variants with the 60-base insertion are designated as insertion forms (Ik1+, Ikx+, etc.). Lengths of expected PCR products are shown in parentheses.

 
Products ~60 bases longer than Ik1, Ikx, Ik2, and Ik4 were detected in normal cord blood and bone marrow and the three ALL cell lines (Fig. 3Go). Faint bands ~60 bases longer than Ik7 and Ik8 were also observed in some normal and malignant samples (Fig. 3Go). DNA sequencing revealed that each of these products was identical with the parent isoform but with a 60-base insertion following exon 2 (Fig. 3Go). The 60-base insertion was identical with that identified in Ik2 RT-PCR products generated from ALL patient samples (9, 10). Thus, Ikaros isoforms with the 30-base deletion, as well as multiple DNA binding and nonbinding Ikaros isoforms with the 60-base insertion previously linked to leukemia, are expressed at the RNA level in normal hemopoietic cells.

The new Ikaros isoform is the predominant Ikaros protein in normal human hemopoietic cells, but not in leukemia cell lines

Immunoblots specific to all Ikaros isoforms detected longer DNA-binding (>46 kDa) and shorter DNA nonbinding Ikaros proteins (>46 kDa) in normal and leukemia cells (Fig. 4GoA). However, different isoforms predominated in normal cord blood and bone marrow than in the three leukemia cell lines, each of which showed a similar pattern of expression.



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  		FIGURE 4. A previously unidentified Ikaros isoform and its insertion form are the predominant Ikaros proteins in normal cord blood and bone marrow, but not leukemia cell lines. Immunoblots performed on total cell lysates from equivalent numbers of indicated cells. Predicted molecular mass based on amino acid sequence is shown in parentheses. A, Detection of Ikaros proteins with a combination of Abs specific to the N terminus (anti-NTS) and C terminus (anti-CTS) common to all Ikaros isoforms. B, Detection of Ikaros proteins with an Ab specific to the residues encoded by the 60-base insert (anti-IkH). C, Detection of Ikaros proteins in cord blood with Abs specific to the N terminus common to all Ikaros isoforms (i (anti-NTS) and ii (M20)); Abs specific to the C terminus common to all Ikaros isoforms (iii (anti-CTS); and iv (E20)); and an Ab (2A9) specific to exon 3 common to Ik1, Ikx, Ik3, and Ik5.

 
Bands consistent in size with Ik1, Ik2, and their associated insertion or deletion forms were detected in all cell types (Fig. 4GoA). The predominant band in normal cord blood and bone marrow was a broad dense band consistent in size with Ikx and its insertion and deletion forms (Fig. 4GoA). However, the three leukemia cell lines showed only a faint cluster of bands at this molecular mass. A band consistent in size with that for Ikx was similarly detected in immunoblots of cord blood using four different anti-Ikaros Abs (Fig. 4GoC, i–iv). In addition, Ikx and a faint cluster of bands representing Ik1 forms were detected with a murine mAb specific to exon 3 (Exon 3 is present in Ik1, Ikx, Ik3, and Ik5 but absent from other Ikaros isoforms, including Ik2; Fig. 4GoCv.). Thus, in normal human hemopoietic cells, but not in leukemia cell lines, the predominant Ikaros protein expressed is Ikx.

Ikaros proteins with the insertion are present in normal hemopoietic cells and leukemia cell lines

Immunoblots performed with Abs specific to the residues encoded by the 60-base insert (Fig. 4GoB) showed that human cells express insertion forms of longer DNA-binding isoforms (Ik1, Ikx, and Ik2/Ik3) and shorter, DNA nonbinding forms. Although proteins with the insert were expressed in normal and leukemia cells, the pattern of protein expression was again different between normal and malignant cells. Ikx+ predominated in normal, but not malignant cells.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
To determine the extent to which novel human Ikaros splice variants were unique to leukemia, we studied Ikaros expression in two normal human hemopoietic sources, umbilical cord blood and bone marrow. These sources ensured that our analysis would include Ikaros isoforms in a range of hemopoietic lineages and during all stages of differentiation. We also examined Ikaros expression in three ALL cell lines used in previous studies (9, 10).

Our RT-PCR assays confirmed reports of Ikaros mRNA with the 30-base deletion in normal hemopoietic tissues (13) and extended these findings to identify transcripts specific for deletion forms of Ik1 and a new Ikaros isoform designated Ikx (Fig. 2Go). We detected transcripts with the 60-base insert in Ik1, Ik2, Ik4, Ik7, Ik8, and the new isoform, Ikx, in normal and leukemia cells (Fig. 3Go). Thus, normal human hemopoietic cells as well as leukemia cell lines generate message for a variety of DNA-binding and nonbinding Ikaros isoforms including many with the 60-base insert or 30-base deletion.

The RT-PCR assays described here are very useful in identifying the particular Ikaros transcripts generated within normal and leukemia cells. However, both of our primer pairs amplify multiple cDNAs with ability to compete for primers that may vary depending on PCR conditions or inherent differences in cDNA. Thus, these assays do not permit quantitative assessment of mRNA expression or address the critical question of whether novel Ikaros transcripts are expressed as proteins. This is especially important given that mRNA expression often correlates poorly with protein expression. Therefore, we examined the expression of Ikaros proteins by immunoblot using Abs that were specific to the residues encoded by the 60-base insertion as well as Abs that could detect all Ikaros isoforms.

Our studies are the first to show that Ikaros proteins containing the sequence encoded by the 60-base insert are present in human cells. Evidence for the expression of Ikaros proteins with the deletion was less clear. Immunoblots specific to forms of Ikaros with the insertion showed a clear doublet the approximate size of Ik1 in leukemia cell lines (Fig. 4GoB). The lower band in this pair may represent a form of Ik1 that includes both the insertion and deletion. PCR assays described here were not designed to detect the presence of the insertion and deletion in the same isoform. However, transcripts for a form of Ik2 with both the insertion and deletion have been detected in leukemia patient samples and in the Molt-3 cell line (9, 10).

Our studies demonstrated that expression of proteins representing Ikaros insertion forms and DNA nonbinding Ikaros isoforms is not limited to malignant cells. However, there were differences in the pattern of Ikaros protein expression between normal and leukemia cells. Ik1 and Ik1+ predominated in the leukemia cell lines, while Ikx and Ikx+ predominated in normal cord blood and bone marrow (Fig. 4Go).

Ikx, the new Ikaros isoform, is similar to Ik3, but it includes exon 6. Immunoblots performed with six anti-Ikaros Abs detected a broad band consistent with the predicted size of Ikx and its insertion and deletion forms (Fig. 4Go). Bands consistent in size with previous reports of Ik1 (10, 12, 14) were observed just above Ikx, and others the predicted size of both Ik2 and Ik3 forms (47–50.5 kDa) were detected just below Ikx. These likely represent Ik2, because transcripts for Ik3 were not detected by RT-PCR assay in either normal or leukemia cell lines (Fig. 2Go). The band representing Ikx was recognized by an Ab specific to Ikaros exon 3 (Fig. 4GoCv), ruling out the possibility that this protein was Ik2 (Ik2 does not include exon 3). Although Ikx has not been described before, PCR products and proteins consistent in size with that expected for the new isoform can be observed in data published in several previous studies (8, 9, 10, 12, 14). The predominance of Ikx in normal hemopoietic cells suggests that it may play a significant role in normal human hemopoiesis. Further studies are needed to determine whether the relatively low levels of Ikx in leukemia cells play a role in malignancy.


   Acknowledgments
 
We thank Sinisa Dovat and Bradley Cobb for helpful discussions and the laboratory of Stephen Smale for the generous gift of anti-Ikaros Abs.


   Footnotes
 
1 This work is supported by National Institutes of Health Grants R01DK54567 and 2P50HL54850 (to G.M.C.), National Research Service Award 1F32DK10101 (to K.J.P.), and a Fellowship from the Childrens Hospital Los Angeles Research Institute (to K.J.P.). G.M.C. is a Scholar of the Leukemia and Lymphoma Society. Back

2 Address correspondence and reprint requests to Dr. Kimberly J. Payne, Childrens Hospital Los Angeles, MS#62, 4650 Sunset Boulevard, Los Angeles, CA 90027. E-mail address: kpayne{at}usc.edu Back

3 Abbreviations used in this paper: Ik, Ikaros isoform; ALL, acute lymphocytic leukemia; CTS, C-terminal sequence; NTS, N-terminal sequence. Back

Received for publication May 17, 2001. Accepted for publication June 26, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Georgopoulos, K., S. Winandy, N. Avitahl. 1997. The role of the Ikaros gene in lymphocyte development and homeostasis. Annu. Rev. Immunol. 15:155.[Medline]
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  4. Molnár, A., K. Georgopoulos. 1994. The Ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins. Mol. Cell. Biol. 14:8292.[Abstract/Free Full Text]
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  6. Sun, L., A. Liu, K. Georgopoulos. 1996. Zinc finger-mediated protein interactions modulate Ikaros activity, a molecular control of lymphocyte development. EMBO J. 15:5358.[Medline]
  7. Cobb, B. S., S. Morales-Alcelay, G. Leiger, K. E. Brown, A. G. Fisher, S. T. Smale. 2000. Targeting of Ikaros to pericentromeric heterochromatin by direct DNA binding. Genes Dev. 14:2146.[Abstract/Free Full Text]
  8. Molnár, A., P. Wu, D. A. Largespada, A. Vortkamp, S. Scherer, N. G. Copeland, N. A. Jenkins, G. Bruns, K. Georgopoulos. 1996. The Ikaros gene encodes a family of lymphocyte-restricted zinc finger DNA binding proteins, highly conserved in human and mouse. J. Immunol. 156:585.[Abstract]
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  10. Sun, L., P. A. Goodman, C. M. Wood, M.-L. Crotty, M. Sensel, H. Sather, C. Navara, J. Nachman, P. G. Steinherz, P. S. Gaynon, et al 1999. Expression of aberrantly spliced oncogenic Ikaros isoforms in childhood acute lymphoblastic leukemia. J. Clin. Oncol. 17:3753.[Abstract/Free Full Text]
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