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From www.bloodjournal.org by guest on June 17, 2017. For personal use only. Reassignment of the Human CSFl Gene to Chromosome lp13-p21 By Stephan W. Morris, Marcus 6. Valentine, David N. Shapiro, Jack E. Sublett, Larry L. Deaven, John T. Foust, W. Mark Roberts, Douglas Pat Cerretti, and A. Thomas Look Human macrophage colony-stimulating factor (CSF-1 or M-CSF) is encoded by a single gene that was previously assigned to the long arm of chromosome 5, band q33.1, in a region adjacent to the gene encoding its receptor (Pettenati MJ, et al, Proc Natl Acad Sei USA 84:2970, 1987). Using fluorescence in situ hybridization with genomic probes to examine normal metaphase chromosomes, we reassigned the human CSFl gene to the short arm of chromosome 1, bands ~ 1 3 . ~ 2 1We . confirmed this result by hybridizing a CSFl cDNA probe to filters containing flow-sorted chromosomes and by identifyingCSFl sequences in DNAs extracted from human x rodent somatic cell hybrids that contained M ACROPHAGE colony-stimulating factor (CSF-1 or M-CSF) stimulates the proliferation and differentiation of mononuclear phagocyte progenitors and promotes the survival and effector functions of mature monocytes and macrophages.' It has been implicated in the growth, maturation, and function of osteoclasts, and alterations of the CSFl gene are responsible for congenital osteopetrosis in up/up mutant mice.*x3 In addition, CSF-1 is produced at high levels by uterine glandular epithelial cells during pregnancy, and may play a role in the formation and differentiation of the p l a ~ e n t a . ~ . ~ Human CSF-1 is encoded by a single gene that spans 20 kb and contains 10 exons'.'; differential splicing generates multiple CSF-1 messenger RNA (mRNA) species with different coding and 3' untranslated sequences.'-" Shortly after human CSFl cDNA and genomic clones were isolated: the gene was mapped by isotopic in situ chromosomal hybridization, together with somatic cell hybrid panels, to chromosome 5 at band q33.1,'* near the gene for its receptor (CSFIR) at 5q33.2-q33.3.'3"5 The CSFl gene appeared to be one of a cluster of growth factor and growth factor receptor genes on the long arm of chromosome 5, which are frequently deleted in bone marrow (BM) cells of patients with myelodysplasia and refractory anemia (so called 5q- syndrome) or therapy-related myeloid leukemias.'6-'8 We began to question the chromosomal location of the CSFl gene while looking for the molecular breakpoints of (3;5)(q25.1;q34) chromosomal translocations in the BM cells of a subset of patients with myeloid leukemia or trilineage marrow dysplasia.'' Hybridization experiments with DNAs from human x hamster hybrid cell lines, containing either the derivative 3 or derivative 5 human chromosomes from leukemic blasts, were inconsistent, leading us to reexamine normal metaphase chromosomes for the location of the CSFl gene. Our results indicate that the gene was incorrectly assigned to chromosome 5q33.1 and, in fact, resides on chromosome 1, at bands p13-p21. This new assignment has important implications for the study of human malignancies with rearrangements of the short arm of chromosome 1 and for studies of the possible involvement of the CSFl gene in human osteopetrosis. Blood, Vol78, No 8 (October 151.1991: pp 2013-2020 human chromosome 1 but not human chromosome 5. Our findings are consistent with studies that have shown tight linkage between the murine CSF7 and amylase genes, as part of a conserved linkage group between mouse chromosome 3 and the short arm of human chromosome 1, which also includes the genes encoding the B subunits of thyrotropin and nerve growth factor. Assignment of the CSF7 gene to chromosome 1 at bands p13-p21 raises the possibility that it may be altered by certain nonrandom chromosomal abnormalities arising in human hematopoietic malignancies and solid tumors. 0 7991 by The American Society of Hematology. MATERIALS AND METHODS Cell lines. DC is a karyotypically normal, Epstein-Barr virus (EBV)-immortalized human lymphocyte cell line; E36 is a hypoxanthine-guanine phosphoribosyl transferase (HPRT)-deficient subclone of V79 Chinese hamster lung fibroblasts; and M613 is a murine HPRT-deficient fibroblast line. The human x mouse somatic cell hybrids CF84-4/4 (repository no. NA09927) and CF84-27/3 (repository no. NA09934) were obtained from the National Institute of General Medical Sciences Human Genetic Mutant Cell Repository (Coriell Institute for Medical Research, Camden, NJ). In addition to small numbers of other human chromosomes, these hybrid cell lines contain either normal human chromosome 1 but not chromosome 5 (CF84-4/4 line) or normal human chromosome 5 but not chromosome 1 (CF84-27/3 line). We derived human x hamster somatic cell lines Al, A4, A5, A6, C1, and C2 by polyethylene glycol (PEG) fusion of cryopreserved leukemic marrow blasts with E36 hamster cells, according to the method of Lemons et al?' A t(3;5)(q25.l;q34) was the only cytogenetic abnormality identified in the leukemic cells of this patient, as reported in a previous study (see results for patient 1 in Raimondi et all'). Hybrid clones contained either the derivative chromosome 3 (Al, A6, and C2) or the derivative chromosome 5 (A4 and A5), together with other human chromosomes. Molecular probes. The 727 bp BamHI CSFl cDNA fragment used for hybridization to Southern blots and filters containing From the Departments of Hematology-Oncology and Tumor Cell Biology, St Jude Children's Research Hospital; the Department of Pediatrics, University of Tennessee, Memphis, College of Medicine, Memphis, TN; the Experimental Pathology Group, Los Alamos National Laboratory, Los Alamos, NM; and the Department of Molecular Biology, Immuner Corporation, Seattle, WA. Submitted April 3,1991; accepted June 20, 1991. Supported in part by Grants No. CA-20180, CA-23099, and CA-21765, from the National Cancer Institute, National Institutes of Health, and by the American Lebanese Syrian Associated Chanties (ALSAC). Address reprint requests to A . Thomas Look, MD, Department of Hematology-Oncology, St Jude Children 's Research Hospital, 332 N Lauderdale, Memphis, TN 38105. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C.section 1734 solely to indicate this fact. 0 1991 by The American Society of Hematology. 0006-4971I91 I7808-OO15$3.OO/O 2013 From www.bloodjournal.org by guest on June 17, 2017. For personal use only. MORRIS ET AL 2014 sorted human chromosomes was obtained from the insert of clone pcDBCSF-4.’ This BamHI fragment, which contains coding sequences from exon 6, was subcloned into pBluescript SK+ (Stratagene Corp, La Jolla, CA) and partially sequenced to confirm its identity. The genomic CSF-1 clones used for fluorescence in situ hybridization were derived from two independent sources. The pMLSV/genomic-CSF-1 clone contains 17.3 kb of human DNA that includes the entire coding sequence of the CSFI gene.” The pHCSF-la genomic clone (no. 40185; American Type Culture Collection [ATCC], Rockville, MD), plaque-purified by us, also contains the complete coding sequence of this gene. Results of restriction mapping of these clones, using the enzymes EamHI, EcoRI, and Hind111 and hybridization of the 727-bp BamHI CSFl cDNA probe to Southern blots prepared after electrophoresis of the fragments in agarose gels, were consistent with published findings.’* The probes for other loci included in this study were a 2.1-kb insert of plasmid pHJ, which contains coding sequences of human juri*'; a 545-bp EcoRIIHindIII genomic fragment from clone pEB8 (ATCC no. 59736), which contains a portion of introns 1 and 2 and all of exon A of the human amylase-1 gene (AMYI)’; the anonymous human chromosome 5 polymorphic probe L1200 (D5S62;Collaborative Research, Inc, Bedford, MA); and a 1.4-kb Sac I genomic fragment immediately 5’ of exon 1 of the human platelet-derivedgrowth factor receptor+ gene (PDGF-Rf3).L‘ Fluorescence in situ hybridization. Bromodeoxyuridine-synchronized, phytohemagglutin-stimulatedperipheral blood lymphocytes from a normal donor were used as a source of metaphase chromosomes. Genomic DNA subcloned into plasmid or phage vectors was nick-translated with digoxigenin-11-UTPand hybridized overnight at 37°C to fixed metaphase chromosomes according to the method of Pinkel et al,24except for the inclusion of 500 pg/mL of highly reiterated human DNA self-annealed to Cot 1 (Bethesda Research Laboratories, Gaithersburg, MD). Signals were detected by incubating the slides with fluorescein-conjugated sheep antidigoxigenin antibodies(Boehringer Mannheim, Indianapolis, IN) followed by counterstaining in propidium iodide solution containing antifade (1,4-diazabicyclo[2.2.2]octane;Sigma Chemical, St Louis, MO). Fluorescence microscopy was performed with a Zeiss standard microscope equipped with fluorescein epifluorescence filters. Sorted human chromosomes. Normal human metaphase chromosomes were isolated from diploid human lymphoblastoid cells or from human x rodent hybrid cell lines and sorted into spots on nitrocellulose filters.z The filters were then hybridized with a ’*P-labeled 727-bp EamHI CSFI cDNA fragment and washed as previously described.% Polymerase chain reaction (PCR). Amplimers specific for the CSFl gene were a 5’ TAACTGGTACAGCCTTGCCC3’ sense strand oligonucleotide and a 5’ TTCCACCTGTCTGTCATCCT3’ antisense strand oligonucleotide. These primers yield an amplified genomic fragment of 1,469-bp, which includes sequences from exons 6 to 8 and the two intervening introns. The CSFIR amplimers (5’ TATACCAATCTGCCGAGCAGC 3’ sense strand and 5’ GGAAGTGGGATCCTCTGAAA3’ antisense strand oligonucleotides) were both derived from exon 22 of the gene and yield a 330-bp product. Amplification was performed in a 50-pL reaction volume containing 200 pmol/L deoxynucleotide triphosphates, 1 pmol/L of each primer, 1.25 U Taq DNA polymerase, and 250 ng of genomic DNA in PCR buffer (Perkin-Elmer Cetus, Norwalk, CT) for 40 cycles (denaturation, 94°C for 1 minute; annealing, 62°C for 2 minutes; extension, 72°C for 3 minutes) in an automated thermocycler (Perkin Elmer-Cetus). The PCR products were separated by electrophoresis on 2% agarose gels, transferred to nylon mem- branes, and hybridized to 32Pend-labeled oligonucleotide probes that contained sequences from either exon 7 of the CSFI gene (5’ CAGAGAGCGGATTCTCCCTTG3‘) or exon 22 of the CSFlR gene (5’ GTTGACGACAGGGAGTACCAC3’). RESULTS Somatic cell hybrids containing derivative t(3;5) chromosomes. Figure 1 shows the results of hybridization experiments to localize the molecular breakpoints of the t(3; 5)(q25.l;q34), using the indicated probes and DNAs from human x hamster hybrid cell lines that contain either the derivative 3 or derivative 5 human chromosome from leukemic blasts. The PDGF-RP gene (located at 5q33-q35) is contained in hybrids with the derivative chromosome 5 (A4 and A5) and in a hybrid with normal chromosome 5 A 8.0 kb PDGF-RP B 2.0 kb D5S62 C 9.4 kb ’ W CSF-1 Fig 1. Southern blot analysis of (A) Hindlll- or (B through D) EcoRI-digested DNAs from human x hamster somatic cell hybrids. Hybridization was performed with probes specific for the PDGF-Rp gene (A), the anonymous chromosome 5 sequence D5S62 (8). the CSFI gene (C), and thejun gene (D). Names of the hybridcell lines, the EBV-transformed human cell line (DC), and the hamster cell line (E36) are indicated above the lanes. The presence of normal (nl) human chromosomes 1,3, and 5, as well as derivative (der) chromosomes 3 or 5, is indicated for each hybrid cell line. The lengths of the human genomic restriction fragments recognized by each probe are also indicatedin kilobases. From www.bloodjournal.org by guest on June 17, 2017. For personal use only. 2015 HUMAN CSFl GENE ON CHROMOSOME 1 (Al), but not in hybrids with the derivative chromosome 3 that lack normal chromosome 5 (A6 and C2; Fig lA), indicating that the PDGF-RP gene maps proximal to the breakpoint. By contrast, the anonymous probe L1200 (DSS62; located at 5q34-qter) hybridized to hybrid DNAs that contained the derivative 3 chromosome, but not to DNAs from hybrids that contained the derivative 5 chromosome (Fig lB), indicating that this sequence lies distal to the breakpoint. Results with the CSFl cDNA probe were inconsistent: there was hybridization to DNAs from two of the hybrid cell lines with the derivative 3 chromosome (A1 and A6), but not to the third (C2; Fig 1C). A similar hybridization pattern was obtained with a jun probe (located at lp32) (Fig 1D) and an AMY1 probe (located at lp21; data not shown), indicating that the short arm of human chromosome 1 is present in hybrids A1 and A6, but not in the other hybrids included in the panel. Fluorescence in situ hybriduation. The lack of a satisfac- A m k t 4 I . jh Fig 2. Fluorescence in situ hybridizationto normal human metaphase chromosomes performed with a genomic fragment that contains the entire coding sequence of the CSFl gene (original magnification x 1,764). Fluorescein fluorescence resulting from hybridization of the probe is evident at identical positions adjacent t o the sister chromatids of chromosome 1 (different metaphase spreads are shown in [A] and [E]). The localization to chromosome 1 at band ~ 1 3 . ~ 2was 1 based on the distance from the centromere of the hybridization signal relative to the entire length of the short arm of chromosome 1. The region of centromeric heterochromatin characteristic of the long arm of chromosome 1, which did not reproduce well in this figure, was readily apparent by microscopic examination, allowing localizationof the fluorescence signal to lp. From www.bloodjournal.org by guest on June 17, 2017. For personal use only. 2016 MORRIS ET AL Fig 3. Localization of the CSFl gene by chromosome sorting. Human chromosomes of each type were sorted by flow cytometry, with greater than 90% purity, directly onto nitrocellulose filter discs (black circles). Chromosomes9 to 12 are shown together and as separate populations obtained by sorting of monochromosome human x rodent somatic cell hybrids. The autoradiograph shows one of two sets of filters hybridized with a 727-bpRs”I CSFl cDNAfragment. tory explanation for the hybridization pattern of the CSFI cDNA probe with DNAs from the somatic cell hybrid cell lines led us to reexamine the chromosomal location of the CSFl gene. We used chromosomal fluorescence in situ hybridization techniques, because they allow unambiguous, high-resolution chromosomal localization of single-copy DNA sequences?427-”When this approach was used with normal human metaphase chromosomes hybridized to a genomic CSF-1 clone (pMLSV/genomic-CSF-l), which includes 17.3 kb of DNA encompassing the entire coding region of the CSFl gene, the only fluorescence signal emanated from the proximal short arm of the chromosome 1 (Fig 2). The hybridizing chromosomal arms were identified as human chromosome l p by the metacentric morphology and characteristicpattern of centromeric heterochromatin on the long arm of this chromosome. Based on the distance from the centromere of the hybridization signal relative to the entire length of the short arm of chromosome 1, we assigned the CSFl gene to bands p13-p21. Specific labeling of 21 of 32 chromosome 1 chromatids at this position was seen in eight representative metaphases selected for photography. Hybridization with an independently derived genomic clone, pHCSF-la, also containing the complete CSFl coding sequence, yielded an identical pattern of fluorescence. A fluorescence signal was not observed on chromosome 5q with either clone. By contrast, cosmid clones containing portions of the CSFIR and PDGF-Rp genesU showed highly specific labeling of the long arm of chromosome 5, as expected, when analyzed by the same techniques (data not shown). Chromosomes isolated by flow sorting. The CSFl gene was independently assigned to chromosome 1 by hybridizing the ’*P-labeled 727-bp CSFI cDNA fragment to filters containing flow cytometrically sorted human metaphase chromosomes. Hybridization was specific for the region of the filters containing chromosome 1 in two independent chromosome-sorting experiments (Fig 3). Specific signals were not observed in regions of the filters containing Fig4. Southem blot analysis of DNAsfrom human x mouse hybrid cell linescontaining human chromosomes 1or 5. Sequential hybridization was performed with probes specific for the PDGf-RB (A),jun (B), or CSf 1 (C) genes t o a Southern blot of Hindlll-digested DNAs from hybrid (CF84-27/3, CF844/4), human (DC), and mouse (M613) cell lines. The presence of human chromosomes 1or 5 is indicated for the somatic cell hybrids. The sizes of human genomic Hindlll fragments recognized by each probe are indicated. From www.bloodjournal.org by guest on June 17, 2017. For personal use only. 2017 HUMAN CSFf GENE ON CHROMOSOME 1 chromosome 5, or in regions containing other human chromosomes. Further studies with DNAs from somatic cell hybrids. We also performed Southern blot analyses of DNAs from hybrids containing human chromosomes 1 or 5. Hybridization with the PDGF-RP probe (Fig 4A), the L1200 probe (D5S62; not shown), jun (Fig 4B), and AMY1 (not shown) confirmed the presence of chromosome 1 (but not chromosome 5 ) in the CF84-4/4 hybrid and chromosome 5 (but not chromosome 1) in the CF84-27/3 hybrid. The CSFI locus cosegregated with chromosome 1, but not with chromosome 5 in these hybrid cell lines (Fig 4C). To exclude the presence of a CSFI pseudogene or related gene on chromosome 1, we performed PCR amplification of DNAs from these hybrids using amplimersspecific for both the CSFI and CSFIR genes. Amplification of total human genomic DNA with a mixture of the two sets of primers resulted in the generation of products of the expected size for both the CSFI (1,469 bp) and CSFIR (330 bp) genes (Fig 5). When the two hybrid DNAs were used as templates with this primer mixture, only the CSFI-specific product was produced with DNA from the chromosome 1-containinghybrid, while only the CSFIR-specific product was observed with DNA from the chromosome 5-contain- A CSF-1 (1469 bp) - CSF-IR (330 bp) - B 1469 bp330 bpCSF-IR Fig 5. PCR analysis of human DNA (DC) and DNAs from human x mouse hybrid cell lines containing human chromosomes 1(CF84-4/4) or 5 (CF84-27/3). An ethidium bromide-stained agarose gel (A) illustrates the products resuking from PCR amplification with a mixture of amplimers specific for the human CSFI and CSFIR genes. End-labeled oligonucleotide probes were used to detect the amplified CSFlR (E) or CSFI (C) genomic fragments in Southern blot analysis of the PCR products. The sizes of the CSFIspecific (1,469 bp) and CSFIR-specific (330bp) PCR products are indicatedto the left of each panel. C 1469 bp330 bp- CSF-1 From www.bloodjournal.org by guest on June 17, 2017. For personal use only. MORRIS ET AL 2018 ing hybrid. Control reactions performed using genomic mouse DNA or in the absence of any template did not yield any amplified products (data not shown). Because the coding sequence flanked by the CSFl exon 6- and exon 8-specific primers is only 569 bp long, amplification of a 1,469-bp product can only result from extension across the two intervening introns, which together are 900 bp in length. DISCUSSION We provide independent lines of evidence that the human CSFl gene is located on chromosome 1, bands p13-p21, rather than on the long arm of chromosome 5, as previously reported.'* This revised assignment of the human CSFl gene is consistent with studies of Gisselbrecht et al,31 who localized the murine CSFl gene to mouse chromosome 3 at band 3F3, both by in situ hybridization and linkage analysis. These investigators observed tight linkage between the murine CSFl and amylase (Amy) genes, indicating that these two loci are separated by approximately 5 centimorgans. The human AMY1 and AMY2 genes are located on chromosome 1 at band ~ 2 1 : ~as part of a conserved linkage group between mouse chromosome 3 and human chromosome 1, which includes the genes encoding the CD2 T-cell surface antigen (CD2), the ATPase a subunit (ATPlAl),and the p subunits of thyroidstimulating hormone (TSHB) and nerve growth factor (NGFB).33*34 Although linkage studies have not been reported with probes from the human CSFl gene, our data combined with linkage studies in the mouse3' suggest that the CSFI locus is part of this evolutionarily conserved linkage group. Recent refinements in chromosomal fluorescence in situ hybridization techniques and chromosome flow sorting have significantly enhanced the accuracy of gene mapping. Previously available methods for in situ hybridization used radioisotopically labeled probes and detection systems based on autoradiographic analysis of silver grains in photographic emulsions applied over metaphase chromosome spreads. These techniques often yielded a low percentage of chromatids with specific hybridization and had a high level of background silver grains, necessitating analysis of large numbers of metaphases to infer statistically the location of sequences hybridizing to the probe. The wide scatter of radioactive disintegrations in the region of hybridization also severely limited the precision of the method. By contrast, fluorescence in situ hybridization techniques generate probe-specific signal in greater than 50% of metaphase chromatids with very low background and the highest resolution attainable by light microscoPY.24.27-30 Paired signals are often evident at symmetrical positions on both chromatids of each metaphase chromosome, as shown in Fig 2, unequivocally localizing the sequences hybridizing with the probe after analysis of relatively few metaphases. Advantages of the fluorescence in situ hybridization method include the ability to order chromosomal loci and determine the approximate genomic distances between probes in both metaphase and interphase c e l l ~ . ~Fluorescence-activated ~.~" flow sorting of chromosomes has also been improved by dual-laser sorting techniques and by the use of chromosome preparations from monochromosome human x rodent hybrids, resulting in the isolation of each human chromosome with greater than 90% purity?' These techniques, combined with PCRbased methods to detect human sequences in wellcharacterized human x rodent somatic cell hybrids, provide sensitive and definitive means to confirm the location of hybridizing sequences at the chromosomal level. Mice with osteopetrosis homozygous for a recessive mutation, op, have a complete systemic deficiency of CSF-1, resulting from a single base-pair insertion in exon sequences that renders the gene incapable of encoding a functional p r ~ t e i n .Human ~ . ~ congenital osteopetrosis resembles the condition in oplop mutant mice; hence, CSFl could be altered in the human autosomal recessive form of this disease. Our results suggest that linkage studies attempting to implicate genetic abnormalities of CSFl in kindreds affected by this disorder should examine polymorphic loci from the linkage group on the short arm of chromosome 1. Abnormalities of chromosome 1 at bands p13-p21 have been observed in both leukemias and solid tumors. A (1;22)(p13;q13) chromosomal translocation is specific for marrow blast cells of infants with acute megakaryoblastic leukemia (FAB M7).35.36Translocations, inversions, and deletions involving this region of the short arm of chromosome 1 have also been identified in lymphoma, breast carcinoma, melanoma, leiomyosarcoma, and mesothelioma?' Thus, the CSFl gene should be considered among the genetic loci that could be affected by these chromosomal alterations in human malignancies. ACKNOWLEDGMENT We are grateful to Drs Martine Roussel and Charles Sherr for encouragement and helpful discussions, for providing the CSFl cDNA probe and CSFlR amplimers, and for comments about the manuscript;to Dr Dirk Bohmann, University of California, Berkeley, for providing the jun cDNA probe; and to Dr Barbara Weiffenbach, Collaborative Research, Bedford, MA, for access to human chromosome 5 linkage data before publication. We thank Sharon Nooner, Bart Jones, Kevin Coleman, and Mary Campbell for technical assistance and John Gilbert for editorial review. REFERENCES 1. Sherr CJ, Stanley ER: Colony-stimulating factor 1 (macrophage colony-stimulating factor), in Sporn MB, Roberts AB (eds): Handbook of Experimental Pharmacology, Peptide Growth Factors and Their Receptors I (vol 95/I). New York, NY, SpringerVerlag, 1990, p 667 2. Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD, Nishikawa SI: The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345:442,1990 3. Wiktor-JedrzejczakW, Bartocci A, Ferrante AW Jr, Ahmed- From www.bloodjournal.org by guest on June 17, 2017. For personal use only. HUMAN CSFI GENE ON CHROMOSOME 1 Ansari A, Sell KW, Pollard JW, Stanley ER: Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (oplop) mouse. Proc Natl Acad Sci USA 87:4828,1990 4. 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Kawasaki ES, Ladner MB, Wang AM, Van Arsdell J, Warren MK, Coyne MY, Schweickart VL, Lee MT, Wilson KJ, Boosman A, Stanley ER, Ralph P, Mark DF: Molecular cloning of a complementary DNA encoding human macrophage-specific colonystimulating factor (CSF-1). Science 230:291, 1985 10. Wong GG, Temple PA, Leary AC, Witek-Giannotti JS, Yang YC, Ciarletta AB, Chung M, Murtha P, Kriz R, Kaufman RJ, Ferenz CR, Sibley BS, Turner KJ, Hewick RM, Clark SC, Yanai N, Yokota H, Yamada M, Saito M, Motoyoshi K, Takaku F Human CSF-1: Molecular cloning and expression of 4-kb cDNA encoding the human urinary protein. Science 235:1504, 1987 11. Rettenmier CW, Roussel MF: Differential processing of colony-stimulating factor 1 precursors encoded by two human cDNAs. Mol Cell Biol8:5026,1988 12. Pettenati MJ, Le Beau MM, Lemons RS, Shima EA, Kawasaki ES, Larson RA, Sherr CJ, Diaz MO, Rowley JD: Assignment of CSF-1 to 5q33.1: Evidence for clustering of genes regulating hematopoiesis and for their involvement in the deletion of the long arm of chromosome 5 in myeloid disorders. Proc Natl Acad Sci USA 84:2970,1987 13. Roussel MF, Sherr CJ, Barker PE, Ruddle FH: Molecular cloning of the c-fms locus and its assignment to human chromosome 5. J Virol48:770,1983 14. Groffen J, Heisterkamp N, Spurr N, Dana S, Wasmuth JJ, Stephenson JR: Chromosomal localization of the human c-fms oncogene. Nucleic Acids Res 11:6331,1983 15. Le Beau MM, Westbrook CA, Diaz MO, Larson RA, Rowley JD, Gasson JC, Golde DW, Sherr CJ: Evidence for the involvement of GM-CSF and fms in the deletion (5q) in myeloid disorders. Science 231:984,1986 16. Le Beau MM, Pettenati MJ, Lemons RS, Diaz MO, Westbrook CA, Larson RA, Sherr CJ, Rowley JD: Assignment of the GM-CSF, CSF-1, and FMS genes to human chromosome 5 provides evidence for linkage of a family of genes regulating hematopoiesis and for their involvement in the deletion (5q) in myeloid disorders. Cold Spring Harb Symp Quant Biol 515399, 1986 17. Nagarajan L, Lange B, Cannizzaro L, Finan J, Nowell PC, Huebner K: Molecular anatomy of a 5q interstitial deletion. Blood 75:82, 1990 18. Huebner K, Nagarajan L, Besa E, Angert E, Lange BJ, 2019 Cannizzaro LA, Van den Berghe H, Santoli D, Finan J, Croce CM, Nowell PC: Order of genes on human chromosome 5q with respect to 5q interstitial deletions. Am J Hum Genet 4626, 1990 19. Raimondi SC, Dube ID, Valentine MB, Mirro J Jr, Watt HJ, Larson RA, Bitter MA, Le Beau MM, Rowley JD: Clinicopathologic manifestations and breakpoints of the t(3;5) in patients with acute nonlymphocytic leukemia. Leukemia 3:42,1989 20. Lemons RS, Eilender D, Waldmann RA, Rebentisch M, Frej AK, Ledbetter DH, Willman C, McConnell T, O’Connell P: Cloning and characterization of the t(15;17) translocation breakpoint region in acute promyelocytic leukemia. Genes Chromosomes Cancer 2:79,1990 21. Bohmann D, Bos TJ, Admon A, Nishimura T, Vogt PK, Tjian R: Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1. Science 238:1386,1987 22. Gumucio DL, Wiebauer K, Caldwell RM, Samuelson LC, Meisler MH: Concerted evolution of human amylase genes. Mol Cell Biol8:1197,1988 23. Roberts WM, Look AT, Roussel MF, Sherr CJ: Tandem linkage of human CSF-1 receptor (c-fms) and PDGF receptor genes. Cell 55:655,1988 24. Pinkel D, Landegent J, Collins C, Fuscoe J, Segraves R, Lucas J, Gray J: Fluorescence in situ hybridization with human chromosome-specific libraries: Detection of trisomy 21 and translocations of chromosome 4. Proc Natl Acad Sci USA 85:9138,1988 25. 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Dracopoli NC, Stanger BZ, Ito CY, Call KM, Lincoln SE, Lander ES, Housman DE: A genetic linkage map of 27 loci from From www.bloodjournal.org by guest on June 17, 2017. For personal use only. MORRIS ET AL 2020 PND to FY on the short arm of human chromosome I. Am J Hum Genet 43:462,1988 35. Sait SN, Brecher ML, Green DM, Sandberg AA: Translocation t(1;22) in congenital acute megakaryocytic leukemia. Cancer Genet Cytogenet 34277,1988 P, Emami A, Gross S, Alvarado C, Phillips C, Krischer J, Crist W, Head D, Gresik M, Ravindranath Y, Weinstein H: The t(1;22)(p13; q13) is nonrandom and restricted to infants with acute megakaryoblastic leukemia. Blood 1991 (in press) 37. Trent JM, Kaneko Y, Mitelman F: Report of the committee on structural chromosome changes in neodasia. Cvtogenet Cell Genet 51533,1989 v 36. Carroll A, Civin C, Schneider N, Dah1 G, Pappo A, Bowman , Y From www.bloodjournal.org by guest on June 17, 2017. For personal use only. 1991 78: 2013-2020 Reassignment of the human CSF1 gene to chromosome 1p13-p21 SW Morris, MB Valentine, DN Shapiro, JE Sublett, LL Deaven, JT Foust, WM Roberts, DP Cerretti and AT Look Updated information and services can be found at: http://www.bloodjournal.org/content/78/8/2013.full.html Articles on similar topics can be found in the following Blood collections Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. 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