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Chronic myeloid leukemia is fundamentally a genetic disorder, specifically a somatic cell genetic disorder, which has environmental causes such as irradiation and chemical (e.g., benzene) exposure (Jacobs, 1989). Fitzgerald (1976) described a family in which a man and 2 of his 3 children had a Philadelphia-like chromosome t(11;22)(q25;q13). The fact that they did not have leukemia or other hematologic disorder was thought by Fitzgerald to relate to the finding that the break in chromosome 22 was distal to that in CML. In these cases it was at the q12-q13 interface, whereas in the Philadelphia chromosome it is at the q11-q12 band interface. Thus the 22q12 band may contain critical genetic material concerned with normal (and abnormal) myeloid proliferation. The Philadelphia chromosome of chronic myeloid leukemia (a G group chromosome with part of its long arm missing) was found by Nowell and Hungerford in 1960. It was presumed to be a deleted chromosome 21, the same chromosome as that which is trisomic in Down syndrome (190685). The elevated alkaline phosphatase activity in Down syndrome and depressed activity in CML was viewed as consistent with this interpretation. (It was called the Philadelphia chromosome because it was thought to be useful to follow the practice of hemoglobinologists and name anomalous chromosomes after the city of discovery.) Using the improved definition provided by 'banding' methods, Rowley (1973) showed that in fact there is a translocation of the distal part of chromosome 22 (not 21) onto another chromosome, usually 9q. Court Brown and Doll (1965) followed up more than 14,000 patients irradiated in the treatment of ankylosing spondylitis in British clinics between 1935 and 1954. A high frequency of Philadelphia-chromosome-positive CML was found. This is an example of a chromosomal change (specific translocation) being the common oncogenetic mechanism for various 'causes' which may include viral infection and chemicals in addition to ionizing radiation.
De Klein et al. (1982) demonstrated that the Abelson oncogene (ABL; 189980) is translocated from chromosome 9 to chromosome 22 in the formation of the Philadelphia chromosome. This indicated that the translocation is reciprocal and suggested a role for the ABL gene in the generation of CML. Not only is the ABL oncogene translocated from 9q to 22 but the SIS oncogene (190040) is presumably translocated from 22 to 9 since it is situated distal to the breakpoint that creates the Philadelphia chromosome (Swan et al., 1982). What is involved in the variant 22q- Philadelphia chromosomes with translocations to other chromosomes? Some 18 different ones were found by Mittelman and Levan (1978). Do all these other chromosomes contribute oncogenes to the 22q- chromosome? Does the translocation of SIS to the recipient chromosome play some role in the usual CML and the variant forms? These were questions raised by Klein (1983), who also asked, Will the microevolutionary process that leads tumor cells towards increased independence from host control, usually referred to as tumor progression, turn out to depend on the sequential activation of multiple oncogenes by genetic rearrangement?
Prakash and Yunis (1984) located the breakpoints in CML to subbands 22q11.21 and 9q34.1. Although the position of the breakpoint in chromosome 9 is quite variable, the breakpoint in chromosome 22 is clustered in an area called bcr for 'breakpoint cluster region.' Shtivelman et al. (1985) referred to bcr as a gene and stated that the ABL oncogene is transferred 'into the bcr gene of chromosome 22.' They found that an 8-kb RNA specific to CML is a fused transcript of the 2 genes. The fused protein is presumably involved in the malignant process. The protein has bcr information at its amino terminus and retains most but not all of the normal abl protein sequences. Since the breakpoint in 9 may be as much as 30 or 40 kb 5-prime to ABL, a large amount must be 'looped out' in the fusion process. The fusion protein has tyrosine kinase activity.
Lillicrap and Sterndale (1984) reported 3 cases of CML in 3 successive generations with a myeloproliferative disorder in a 4th member of the kindred.
About 10% of patients with acute lymphocytic leukemia (ALL; see 159555) have the translocation t(9;22)(q34;q11) indistinguishable from that of CML. Erikson et al. (1986), however, found in 3 of 5 such cases of ALL that the bcr region was not involved and that the 22q11 chromosome breakpoint was proximal (5-prime) to the bcr region. Furthermore, the bcr and c-abl transcripts were of normal size in an ALL line carrying the t(9;22) translocation. The breakpoints of the t(9;22) CML, the t(9;22) of acute lymphocytic leukemia, and the t(8;22) of Burkitt lymphoma fall into 22q11 and are cytologically indistinguishable. By chromosomal in situ hybridization, however, they can be distinguished (Emanuel et al., 1984; Erikson et al., 1986). To this experience, Griffin et al. (1986) added observations on t(11;22), both constitutional and tumor-related (see 133450). In the hybrid gene of CML, the bcr contribution is 5-prime to the abl contribution. In the creation of the gene, splicing can occur across an interval as great as 100 kb. The product of the bcr/abl hybrid gene is a 210-kD protein. It was suggested that the hybrid gene and its product protein be designated PHL. Verhest and Monsieur (1983) found the Philadelphia chromosome in a case of essential thrombocytopenia. Ganesan et al. (1986) found that the BCR gene was rearranged in 7 cases of Philadelphia chromosome-negative CML. In 5 cases hematologic findings were indistinguishable from those of patients with the Philadelphia chromosome. Mes-Masson et al. (1986) isolated overlapping cDNA clones defining the complete coding region for the hybrid protein generated from the ABL and BCR genes. Hariharan and Adams (1987) isolated cDNA clones that collectively spanned the entire BCR coding region. The nucleotide sequence indicated that the BCR polypeptide comprises 1,271 amino acid residues. Stam et al. (1987) showed that the normal gene on chromosome 22 involved at the breakpoint cluster region in the translocation between chromosomes 9 and 22 encodes a 160,000-Da phosphoprotein with serine or threonine kinase activity. Designated PHL, this gene is oriented with its 5-prime end toward the centromere of chromosome 22. As a result of the CML translocation, the 3-prime PHL exons are removed and remain on chromosome 22. The PHL and ABL genes are fused in a head-to-tail fashion.
Schaefer-Rego et al. (1987) found that the breakpoints in 8 of 9 patients in blast crisis were in the 3-prime portion of BCR, whereas the breakpoints in 17 patients in the chronic phase were clustered in the 5-prime portion. Croce et al. (1987) demonstrated that there are in fact 4 BCR genes, all located in the 22q11.2 band. By studying mouse-human hybrid cells with breakpoints at various sites in that region, they concluded that the order of loci is centromere--BCR2, BCR4, IGL--BCR1--BCR3--SIS. This linear order was confirmed by Budarf et al. (1988), who also confirmed that all of the BCR-like genes map proximal to the 22q11-q12 breakpoint of a t(11;22) in a Ewing sarcoma. Hermans et al. (1987) showed that a distinct and different fusion of BCR and ABL occurs in creation of the Philadelphia chromosome associated with acute lymphoblastic leukemia. Rubin et al. (1988) similarly reported a distinctive fusion in acute lymphoblastic leukemia. Mills et al. (1988) found a striking correlation between the site of the breakpoint within BCR and the length of time between presentation and onset of acute phase: on average, patients with a 5-prime breakpoint had a 4-fold longer chronic phase than those with a 3-prime breakpoint. The median times were 203 weeks versus 52 weeks. Grossman et al. (1989) also presented evidence consistent with but not proving a relationship between the site of the breakpoint in BCR and the length of the clinical course before onset of blast crisis. Patients with 3-prime breakpoints progressed to acute disease after a shorter period (average 36.6 months) than did patients with 5-prime breakpoints (average 56.1 months), although the difference was not statistically significant.
To determine whether the P210(bcr/abl) hybrid protein can induce leukemia, Daley et al. (1990) infected murine bone marrow with a retrovirus encoding this protein and transplanted the bone marrow into irradiated syngeneic recipients. Transplant recipients developed several hematologic malignancies, prominent among which was a myeloproliferative syndrome closely resembling the chronic phase of human chronic myelogenous leukemia. Tumor tissue from diseased mice harbored the provirus encoding P210(bcr/abl). Heisterkamp et al. (1990) satisfied Koch postulates in relation to leukemia by demonstrating leukemia in mice transgenic for a bcr/abl p190 construct of the type found in acute lymphoblastic leukemia. Tkachuk et al. (1990) used 2-color fluorescence in situ hybridization (FISH) with probes from portions of the BCR and ABL (189980) genes to detect the BCR-ABL fusion in individual blood and bone marrow cells from 6 patients. The fusion event was detected in all samples analyzed, of which 3 were cytogenetically Ph(1)-negative. One of the Ph(1)-negative samples was also PCR-negative.
The BCR gene is the site of breakpoints used in the generation of the 2 alternative forms of the Philadelphia chromosome translocation found in chronic myeloid leukemia and acute lymphocytic leukemia (Groffen et al., 1984; Shtivelman et al., 1985; Hermans et al., 1987). These alternative breakpoints join different exon sets of BCR to a common subset of the exons of the ABL gene located on chromosome 9. This fusion results in 2 alternative chimeric oncogene products called p210(BCR-ABL) and p185(BCR-ABL). The activation of ABL tyrosine kinase activity is necessary for the oncogenic potential of the chimeric oncogene. Sequences within the first exon of BCR appear to be essential for this activation and probably work through direct physical binding to the kinase regulatory domain of ABL. The normal cellular BCR gene encodes a 160-kD phosphoprotein associated with a serine/threonine kinase activity. Maru and Witte (1991) demonstrated that the first exon of BCR encodes a novel serine/threonine kinase activity.
Haas et al. (1992) demonstrated a 'parent of origin' bias in cases of Philadelphia-chromosome-positive leukemia by use of unique specific chromosome band polymorphisms. They showed that the translocated chromosome 9 was always of paternal origin, whereas the translocated chromosome 22 was derived exclusively from the maternal copy. Preferential retention of paternal alleles has been found in sporadic tumors such as Wilms tumor (194070), rhabdomyosarcoma (268210), osteosarcoma, and retinoblastoma (180200). The finding of preferential participation of the paternally derived chromosome 9 and the maternally derived chromosome 22 in the Ph-translocation strongly indicates that the chromosomal regions involved are imprinted. Feinberg (1993) reviewed 11 examples of preferential parental allelic alterations in cancer. Fioretos et al. (1994) were unable to find evidence for genomic imprinting of the human BCR gene. They identified a BamHI polymorphism in the coding region of BCR exon 1 and by RT-PCR assay showed that both BCR alleles are expressed in the peripheral blood cells of normal persons. Furthermore, Litz and Copenhaver (1994) used PvuII and MaeII restriction site polymorphisms in the BCR gene to study 3 cases of Philadelphia chromosome-positive CML. In all 3 cases, the rearranged allele was paternal in origin. Melo et al. (1994) could find no evidence of parental imprinting of the ABL gene and cited evidence which appeared to exclude imprinting of the BCR gene and to suggest that there is, in fact, no preferential involvement of the maternal BCR or paternal ABL alleles in the formation of the BCR-ABL fusion gene. Melo et al. (1995) further reviewed the evidence they interpreted as indicating that there is no parental bias in the origin of the translocated ABL gene and no evidence for genomic imprinting of ABL in CML. On the other hand, Haas (1995) argued that it still remains likely that ABL and BCR are imprinted.
Using an interspecific backcross, Justice et al. (1990) mapped the Bcr gene to chromosome 10 of the mouse.
The normal BCR gene occupies a region of about 135 kb on chromosome 22. It is expressed as mRNAs of 4.5- and 6.7-kb, which apparently encode for the same cytoplasmic 160-kD protein, and contains 23 exons as well as an unusual inverted repeat flanking the first exon. The BCR protein reportedly contains a unique serine/threonine kinase activity and at least two SH2 binding sites encoded in its first exon and a C-terminal domain that functions as a GTPase activating protein for p21(rac) (Diekmann et al., 1991); see rac serine/threonine protein kinase (164730). Chissoe et al. (1995) sequenced the complete BCR gene and greater than 80% of the human ABL gene, which are both involved in the t(9;22) translocation (Philadelphia chromosome) associated with more than 90% of chronic myelogenous leukemia, 25 to 30% of adult and 2 to 10% of childhood acute lymphoblastic leukemia, and rare cases of acute myelogenous leukemia. Comparison of the gene with its cDNA sequence revealed the positions of 23 BCR exons and putative alternative BCR first and second exons. From the sequence of 4 newly studied Philadelphia chromosome translocations and a review of several other previously sequenced breakpoints, Chissoe et al. (1995) could discern no consistent breakpoint features. No clear-cut mechanism for Philadelphia chromosome translocation was evident.
Sawyers (1999) reviewed the clinical aspects of chronic myeloid leukemia, the molecular aspects of its pathogenesis, and the therapeutic choices available based on new knowledge.
To block BCR/ABL function, Lim et al. (2000) created a unique tyrosine phosphatase by fusing the catalytic domain of SHP1 (604630) to the ABL binding domain of RIN1, an established binding partner and substrate for c-ABL and BCR/ABL. This fusion construct binds to BCR/ABL in cells and functions as an active phosphatase. It effectively suppressed BCR/ABL function as judged by reductions in transformation of fibroblast cells, growth factor independence of hematopoietic cell lines, and proliferation of primary bone marrow cells. In addition, the leukemogenic properties of BCR/ABL in a murine model system were blocked by coexpression of the fusion construct. Expression of the construct also reversed the transformed phenotype of a human leukemia-derived cell line. These results appeared to have direct implications for leukemia therapeutics and suggested an approach to block aberrant signal transduction in other pathologies through the use of appropriately designed escort/inhibitors.
Because tyrosine kinase activity is essential to the transforming function of BCR-ABL, Druker et al. (2001) reasoned that an inhibitor of the kinase may be an effective treatment for CML. They found that indeed a tyrosine kinase inhibitor (STI571) was well tolerated and had significant antileukemic activity in patients with CML in whom treatment with standard chemotherapy had failed. This experience demonstrated the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer.
Druker et al. (2001) found that the same BCR-ABL tyrosine kinase inhibitor was well tolerated and had substantial activity in the blast crises of CML and in Philadelphia-chromosome-positive acute lymphoblastic leukemia. The response was less satisfactory in the ALL group. Goldman and Melo (2001) discussed the likely role of the kinase inhibitor in relation to other forms of therapy for CML. Goldman and Melo (2001) also illustrated the likely mode of action of STI571.
Imatinib (Gleevec, Novartis, Basel, Switzerland), formerly referred to as STI571, was approved by the Food and Drug Administration in May 2001 for the treatment of CML that is refractory to interferon therapy and in February 2002 for the treatment of gastrointestinal stromal tumors (606764), which can be caused by mutations in the KIT gene (164920) (Savage and Antman, 2002). In both cases the agent works as an inhibitor of specific protein tyrosine kinases.
Barbany et al. (2002) described a patient in whom complete molecular response was achieved with no evidence of BCR-ABL mRNA 6 months after treatment with imatinib was begun. The patient was a 58-year-old man with Philadelphia chromosome-positive CML in chronic phase. He was initially treated with interferon alfa followed by intensive chemotherapy plus granulocyte colony-stimulating factor, which allowed the successful collection of Ph-negative blood stem cells. Subsequently, he underwent autologous blood stem cell transplantation. Cytogenetic relapse was detected 34 months after transplantation in a routine blood marrow examination. Treatment with interferon alfa was reinstated but had to be discontinued because of side effects (depression) with no signs of cytogenetic response. Treatment with imatinib was then initiated.
Laurent et al. (2001) reviewed the role of BCR alone or when joined with ABL (189980) in normal and leukemic pathophysiology.
Clinical studies with the Abl tyrosine kinase inhibitor STI571 in CML demonstrated that many patients with advanced-stage disease respond initially but then relapse. Through biochemical and molecular analysis of clinical material, Gorre et al. (2001) found that the drug resistance was associated with a reactivation of BCR-ABL signal transduction in all cases examined. In 6 of 9 patients, resistance was associated with a single amino acid substitution in a threonine residue of the Abl kinase domain known to form a critical hydrogen bond with the drug. This substitution of threonine with isoleucine was sufficient to confer STI571 resistance in a reconstitution experiment. In 3 patients, resistance was associated with progressive BCR-ABL gene amplification. Gorre et al. (2001) concluded that their studies provided evidence that genetically complex cancers retain dependence on an initial oncogenic event and suggest a strategy for identifying inhibitors of STI571 resistance.
Azam et al. (2003) stated that sequencing of the BCR-ABL gene in patients who relapsed after STI571 chemotherapy revealed a limited set of kinase domain mutations that mediate drug resistance. To obtain a more comprehensive survey of the amino acid substitutions that confer STI571 resistance, they performed an in vitro screen of randomly mutagenized BCR-ABL and recovered all the major mutations previously identified in patients and numerous others that illuminated novel mechanisms of acquired drug resistance. Structural modeling implied that a novel class of variants acts allosterically to destabilize the autoinhibited conformation of the ABL kinase, to which STI571 preferentially binds. The authors concluded that this screening strategy is a paradigm applicable to a growing list of target-directed anticancer agents and provides a means of anticipating the drug-resistant amino acid substitutions that are likely to be clinically problematic.
Olavarria et al. (2002) described a male patient who had a relapse to chronic phase after stem cell transplantation for CML and did not benefit from treatment with donor lymphocyte infusion. After 6 months of therapy with STI571, the patient had a rapid, complete hematologic response, and complete restoration of donor-type hematopoiesis, with 100% female marrow metaphases, although RT-PCR still detected BCR-ABL transcripts in the blood at low level.
The arrest of differentiation is a feature of chronic myelogenous leukemia cells both in myeloid blast crisis and in myeloid precursors that ectopically express the p210(BCR-ABL) oncoprotein. Related to the underlying mechanisms of this arrest of differentiation, Perrotti et al. (2002) showed that expression of BCR-ABL in myeloid precursor cells leads to transcriptional suppression of the gene encoding granulocyte colony-stimulating factor receptor (CSF3R; 138971), possibly through downmodulation of C/EBP-alpha (116897), the principal regulator of granulocytic differentiation. Expression of C/EBP-alpha protein is barely detectable in primary marrow cells taken from individuals affected with chronic myeloid leukemia in blast crisis. In contrast, CEBPA RNA is clearly present. Further experiments by Perrotti et al. (2002) indicated that BCR-ABL regulates the expression of C/EBP-alpha by inducing heterogeneous nuclear ribonucleoprotein E2 (PCBP2; 601210).
Demiroglu et al. (2001) described 2 patients with a clinical and hematologic diagnosis of CML in chronic phase who had an acquired t(8;22)(p11;q11). They confirmed that both patients were negative for a BCR-ABL fusion gene and that both had an in-frame mRNA fusion between BCR exon 4 and FGFR1 (136350) exon 9. Thus, a BCR-FGFR1 fusion may occur in patients with apparently typical CML. The possibility of successful treatment with specific FGFR1 inhibitors was suggested.
Saglio et al. (2002) found that a patient with a typical form of chronic myeloid leukemia carried a large deletion on the derivative chromosome 9q+ and an unusual BCR-BCL transcript characterized by the insertion, between BCR exon 14 and ABL exon 2, of 126 bp derived from a region located on chromosome 9, 1.4 Mb 5-prime to ABL. This sequence was contained in a bacterial artificial chromosome (BAC), which in FISH experiments on normal metaphases was found to detect, in addition to the predicted clear signal at 9q34, a faint but distinct signal at 22q11.2, where the BCR gene is located, suggesting the presence of a large region of homology between the 2 chromosome regions. A BLAST analysis of the particular BAC sequence against the entire human genome revealed the presence of a stretch of homology, about 76 kb long, located approximately 150 kb 3-prime to the BCR gene, and containing the 126-bp insertion sequence. Evolutionary studies using FISH identified the region as a duplicon, which transposed from the region orthologous to human 9q34 to chromosome 22 after the divergence of orangutan from the human-chimpanzee-gorilla common ancestor about 14 million years ago. Saglio et al. (2002) noted that sequence analyses reported as part of the human genome project had disclosed an unpredicted extensive segmental duplication in the human genome, and the impact of duplicons in triggering genomic disorders is becoming more and more apparent. The discovery of a large duplicon relatively close to the ABL and BCR genes and the finding that the 126-bp insertion is very close to the duplicon at 9q34 open the question of the possible involvement of the duplicon in the formation of the Philadelphia chromosome translocation.
Baxter et al. (2002) reported the identification and cloning of a rare variant translocation, t(4;22)(q12;q11), in 2 patients with a CML-like myeloproliferative disease. An unusual inframe BCR/PDGFRA (173490) fusion mRNA was identified in both patients, with either BCR exon 7 or exon 12 fused to short BCR intron-derived sequences, which were in turn fused to part of PDGFRA exon 12. Sequencing of the genomic breakpoint junctions showed that the chromosome 22 breakpoints fell in BCR introns, whereas the chromosome 4 breakpoints were within PDGFRA exon 12.
RNA interference (RNAi) is a highly conserved regulatory mechanism that mediates sequence-specific posttranscriptional gene silencing initiated by double-stranded RNA (dsRNA) (Fire, 1999). Fusion transcripts encoding oncogenic proteins may represent potential targets for a tumor-specific RNAi approach. Scherr et al. (2003) demonstrated that small interfering RNAs (siRNAs) against BCR-ABL specifically inhibited expression of BCR-ABL mRNA in hematopoietic cell lines and primary CML cells.
When the Philadelphia-chromosome-positive chronic myeloid leukemia-blast crisis cell line BV173 is injected into SCID mice, a disease process closely resembling that seen in leukemia patients results. For example, BCR-ABL transcripts are detectable in bone marrow, spleen, peripheral blood, liver, and lungs. Skorski et al. (1994) found that systemic treatment of the leukemic mice with a 26-mer BCR-ABL antisense oligodeoxynucleotide induced disappearance of leukemic cells and a marked decrease in BCR-ABL mRNA in mouse tissues. Untreated mice or mice treated with a BCR-ABL sense oligodeoxynucleotide or a 6-base-mismatched antisense oligodeoxynucleotide were dead 8 to 13 weeks after leukemia cell injection; in marked contrast, mice treated with BCR-ABL antisense oligodeoxynucleotide died of leukemia 18 to 23 weeks after injection of leukemic cells. Findings were interpreted as indicating the in vivo effectiveness of an anticancer therapy based on antisense oligodeoxynucleotides targeting a tumor-specific gene.
Cancer is thought to arise from multiple genetic events that establish irreversible malignancy. A different mechanism might be present in certain leukemias initiated by a chromosomal translocation. Huettner et al. (2000) adopted a new approach to determine if ablation of the genetic abnormality is sufficient for reversion. They generated a conditional transgenic model of BCR-ABL-induced leukemia. The most common form of the product of the fusion gene, p210 BCR-ABL1, is found in more than 90% of patients with chronic myelogenous leukemia and in up to 15% of adult patients with de novo acute lymphoblastic leukemia. Efforts to establish a useful transgenic model had been hampered by embryonic lethality when the oncogene is expressed during embryogenesis, by reduced penetrance, or by extremely long latency. Huettner et al. (2000) used the 'knock-in' approach to induce leukemia by p190 BCR-ABL1 (Castellanos et al., 1997). Lethal leukemia developed within an acceptable time frame in all animals, and complete remission was achieved by suppression of BCR-ABL1 expression, even after multiple rounds of induction and reversion. The results demonstrated that BCR-ABL1 is required for both induction and maintenance of leukemia. The findings suggested that complete and lasting remissions can be achieved if the genetic abnormality is abolished or silenced before secondary mutations are acquired. The results have implications for therapies that directly target leukemia oncogenes, with a relevant example being the use of BCR-ABL1-specific tyrosine kinase inhibitors.
Tanabe et al. (2000) designed a ribozyme which exclusively targets the junction sequence of BCR-ABL and showed that it specifically cleaves the BCR-ABL mRNA, inducing apoptosis in CML cells. Tanabe et al. (2000) tested this technology in vivo by embedding genes encoding the maxizyme downstream of genes for the human tRNA. They used a retroviral system for the expression of the maxizyme in leukemic cells. A line of CML cells was transduced either with a control vector in which the maxizyme sequence had been deleted or with the maxizyme-encoding vector. They then injected 2 x 10(6) transduced cells into the tail veins of NOD-SCID mice. Animals transduced with the control vector died between 6 and 13 weeks afterwards due to diffuse leukemia. Animals treated with the BCR-ABL ribozyme all survived, with no evidence of leukemia in 8 animals 8 weeks after inoculation. Tanabe et al. (2000) stated that their maxizyme could be useful for purging bone marrow in cases of CML treated by autologous transplantation, when it would presumably reduce the incidence of relapse by decreasing the tumorigenicity of contaminating CML cells in the transplant.
Grosveld et al. (1986); Heisterkamp et al. (1985); Koeffler and Golde (1981); Kohno and Sandberg (1980); Nowell and Hungerford (1960); Nowell and Hungerford (1960); Pegoraro et al. (1983); Priest et al. (1980); Shtivelman et al. (1987); Stam et al. (1985); Teyssier et al. (1985); Verma and Dosik (1980)
Victor A. McKusick - updated : 5/16/2003Stylianos E. Antonarakis - updated : 4/14/2003George E. Tiller - updated : 2/25/2003Victor A. McKusick - updated : 9/26/2002Victor A. McKusick - updated : 9/20/2002Victor A. McKusick - updated : 7/1/2002Victor A. McKusick - updated : 3/14/2002Victor A. McKusick - updated : 1/14/2002Ada Hamosh - updated : 8/27/2001Victor A. McKusick - updated : 5/18/2001Victor A. McKusick - updated : 4/25/2001Victor A. McKusick - updated : 11/27/2000Ada Hamosh - updated : 8/2/2000Victor A. McKusick - updated : 12/28/1999Victor A. McKusick - updated : 5/6/1999
Victor A. McKusick : 6/2/1986
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