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PubMed1993

Nucleotide sequence analysis of human T cell leukemia virus, type II (HTLV-II) isolates.

A study by Hall et al. (J Virol 1992;66:2456-2463; Ref. 11) has suggested the existence of two closely related molecular subtypes of HTLV-II, which were tentatively designated HTLV-IIa and HTLV-IIb. To confirm this nucleotide sequence analysis of 986 bp of the env gene region encoding the entire surface glycoprotein, gp46, and the amino terminus of the transmembrane glycoprotein, gp21, of 10 HTLV-II isolates was carried out. The results clearly established the existence of two subtypes and demonstrated a 4.3% divergence in sequence in this region. Analysis of other gene regions of the provirus, including the pol (1544 bp), gag (448 bp), and the entire LTR (743 bp) of two representative isolates of each subtype, showed a sequence divergence of 3.8 to 5.7%, with greatest divergence occurring in the LTR. In addition to single nucleotide changes, the gag regions encoding the structural protein, p19, of the HTLV-IIb isolates were also found to have a 66-bp deletion that would be expected to result in a p19 protein having a 22-amino acid deletion in the carboxy-terminus region. Attempts to exploit this to differentiate the two subtypes serologically were unsuccessful in that recombinant p19 proteins of both subtypes were found to be antigenically cross-reactive. The finding of two molecular subtypes of HTLV-II may have important implications for a better understanding of the biological and pathogenic properties of the virus, and will be useful in characterizing the viruses present in endemic foci in American Indian populations.

Amino Acid Sequence↗
PubMed2005

Gene expression profiling of localized esophageal carcinomas: association with pathologic response to preoperative chemoradiation.

PURPOSE: Patients with localized esophageal carcinoma have a 5-year survival rate of less than 20%. Patients are often treated similarly (ie, with preoperative chemoradiotherapy) but the outcomes vary greatly. Chemoradiotherapy and surgery can result in significant undesirable consequences. Currently, however, there are no tools to help select optimum therapy. We hypothesized that gene expression profiling could provide clues and biomarkers for selection of therapy. METHODS: Pretreatment endoscopic cancer biopsies from 19 patients (16 with adenocarcinoma, two with squamous cell carcinoma, and one with adenosquamous carcinoma) enrolled onto a preoperative chemoradiotherapy protocol were profiled using oligonucleotide microarrays. Surgical specimens following therapy were assessed for the degree of pathologic response. On the basis of array data, selected genes were analyzed by polymerase chain reaction. RESULTS: Unsupervised hierarchical cluster analysis segregated the cancers into two molecular subtypes, each consisting 10 and nine specimens, respectively. Most cancers (five of six) that had pathologic complete response (pathCR) clustered in molecular subtype I. Subtype II, with one exception, consisted cancers that had less than pathCR (< pathCR). Using a combination marker approach, levels of PERP, S100A2, and SPRR3 allowed discrimination of pathCR from < pathCR with high sensitivity and specificity (85%). Pathway analysis identified apoptotic pathway as one of the key functions downregulated in molecular type II in comparison with type I. CONCLUSION: These encouraging, albeit preliminary, data suggest that expression profiling may distinguish cancers with different pathologic outcome. This is the first report to show subtypes of esophageal cancers with distinct molecular signatures. The potential of PERP, S100A2, and SPRR3 as biomarkers of pathCR warrants further validation.

Adenocarcinoma↗
PubMed2003

Cell cycle behavior of human HP1 subtypes: distinct molecular domains of HP1 are required for their centromeric localization during interphase and metaphase.

Heterochromatin protein 1 (HP1) plays an important role in heterochromatin formation. Three subtypes of HP1, namely HP1alpha, beta, and gamma, have been identified in humans. In this study, using yellow fluorescent protein (YFP) fusion constructs, we examined the intracellular localization of human HP1 subtypes during the cell cycle. During interphase, all three HP1 subtypes were localized to centromeric heterochromatin and to promyelocytic leukemia (PML) nuclear bodies. Different preferences, however, were observed among the subtypes: during interphase HP1beta localized most preferentially to centromeric heterochromatin, whereas HP1alpha and gamma were more preferentially localized to PML nuclear bodies. During metaphase, only HP1alpha, was localized to the centromere. We thus determined which molecular domains of HP1 were necessary for their intracellular localization. Our results showed that the C-terminal fragment (amino acid residues 101-180) of HP1alpha was necessary for localization to the metaphase centromere and the N-terminal fragment (amino acid residues 1-76) of HP1beta was necessary for localization to the interphase centromere. Interestingly, simultaneous observations of residues 101-180 of HP1alpha and residues 1-76 of HP1beta in living HeLa cells revealed that during late prophase, the HP1beta fragment dissociated from centromeric regions and the HP1alpha fragment accumulated in centromeric regions. These results indicate that different specific regions of human HP1alpha and HP1beta mediate localization to metaphase and interphase centromeric regions resulting in association of different subtypes of HP1 with the centromere at different times during the cell cycle.

Amino Acid Sequence↗
PubMed2003

Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as adenosine receptor antagonists. Influence of the N5 substituent on the affinity at the human A 3 and A 2B adenosine receptor subtypes: a molecular modeling investigation.

A new series of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines bearing various substituents at both the N5-pyrimidinyl and N8-pyrazolyl positions have been synthesized, and their binding affinities at the four human adenosine receptor subtypes (hA(1), hA(2A), hA(2B), and hA(3)) have been evaluated. All the described compounds contain arylacetyl moieties at the N5 position and arylalkyl substituents at the N8 position. Surprisingly, all the compounds present their most potent affinities at the hA(2B) adenosine receptor with a range of selectivities against the other subtypes. When bulky groups are present simultaneously at the N5 and N8 positions (e.g., compound 9), the best selectivity for the hA(2B) receptor was observed (K(i)(hA(1)) = 1100 nM; K(i)(hA(2A)) = 800 nM; K(i)(hA(2B)) = 20 nM; K(i)(hA(3)) = 300 nM, K(i)(hA(1)/A(2B)) = 55, K(i)(hA(2A)/A(2B)) = 40, K(i)(hA(3)/hA(2B)) = 15). To understand the molecular significance of these results, we compared the putative TM (transmembrane) binding motif of compound 9 on both hA(2B) and hA(3) receptors. From our docking studies, compound 9 fits neatly inside the TM region of the hA(2B) receptor but not in the corresponding hA(3) region, illustrating significant differences between the two subtypes. The study herein presented permits an understanding of why the bioisosteric replacement of an -NH, present in previously reported hA(3) receptor antagonists, with a -CH(2) group at the N5 position induces such large differences in hA(2B)/hA(3) affinity. In the molecular structure of the hA(3) receptor, two residues, Ser243 (TM6) and Ser271 (TM7), create a hydrophilic region, which seems to permit a better accommodation of the phenylurea series into this putative hA(3) binding site than the phenylacetyl series.

Adenosine-5'-(N-ethylcarboxamide)↗
PubMed2000

Waterborne Nosocomial Infections.

Waterborne pathogens cause infections in health-care facilities. Despite guidelines addressing these pathogens, outbreaks and pseudo-outbreaks continue to occur. We reviewed recent reports of infections caused by Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Chryseobacterium species, nontuberculous mycobacteria, and Legionella species. Mycobacterium avium complex (MAC) infection in HIV patients has been linked to hospital water distribution systems; molecular subtyping showed that MAC isolates in patients and hospital water were identical. In immunosuppressed patients, Fusarium infection has been linked to the hospital water distribution system; again molecular subtyping showed that isolates from patients and the water supply were identical. Parasites, especially Cryptosporidium, and viruses have also been implicated in nosocomial infection. Transmission occurs via contact, ingestion, aspiration, or aerosolization of potable water, or via the hands of health-care workers. Interventions designed to interrupt transmission of waterborne pathogens have included the use of antimicrobial handwashes, targeted disinfection of the water supply, and, in high-risk populations, restricting the use of tap water.

Journal Article↗
PubMed2002

Subtyping of bacterial foodborne pathogens.

Phenotype-based and DNA-based subtyping methods allow for differentiation of bacterial isolates beyond the species and subspecies level. Bacterial subtyping methods not only have improved our ability to detect and track foodbome disease outbreaks, but also represent tools to track sources of bacterial contamination throughout the food system. The use of subtyping methods furthermore provides an opportunity to better understand the population genetics, epidemiology, and ecology of different foodbome pathogens. The last 5 years have seen tremendous advancement in the development of sensitive, rapid, automated, and increasingly easy-to-use molecular subtyping methods for a variety of different bacterial foodborne pathogens. This review will highlight key aspects of different subtyping methods for bacterial foodborne pathogens and provide examples of their applications in public health, food safety, epidemiology, and population genetics. Molecular subtyping and characterization methods may also facilitate the development of a novel framework for tracking, preventing, and regulating foodborne bacterial diseases, which is based on evolutionary relationships and genetic characteristics rather than traditional species definitions.

Bacterial Typing Techniques↗
PubMed1996

Polymerase chain reaction--based sequence-specific oligonucleotide hybridization analysis of HLA class II antigens in pulmonary tuberculosis: relevance to chemotherapy and disease severity.

HLA antigens were studied by serology and polymerase chain reaction-based sequence-specific oligonucleotide hybridization techniques in 153 patients with pulmonary tuberculosis (PTB) and 289 healthy controls. HLA-DR2 was present more frequently in PTB patients than in controls (51% vs. 36.3%; corrected P[Pc]=.029, relative risk [RR] = 1.8). The DR2 association was stronger in patients in the drug-failure group (n=56; Pc=.000012, RR=3.7) than in healthy controls and in patients in the drug-responder group. No significant deviation was observed in HLA allelic frequencies in various patient groups, as determined by radiographs of lung lesions. Molecular subtyping of DR2 revealed that the bulk of the allele was DRB1*1501 and DRB1*1502 in patients and controls. There was no skewing of the frequency of these molecular subtypes of DR2 in patients, suggesting that the whole DR2 molecule or its closely linked gene(s) may be involved in governing patient susceptibility to PTB and, particularly, development of the severe drug-resistant form of the disease.

Adult↗
PubMed2006

Rapid diagnosis of avian influenza (AI) and assessment of pathogenicity of avian H5 and H7 subtypes by molecular methods.

Avian influenza (AI) is a highly contagious viral disease of poultry that is found worldwide. There are two forms of AI: a mild form called low pathogenicity avian influenza (LPAI), and a severe form called highly pathogenic avian influenza (HPAI). HPAI is associated with the H5 and H7 subtypes of AI virus (AIV) and is subject to Federal control and International reporting. A real-time reverse transcription-polymerase chain reaction (rRT-PCR) assay has been developed and validated that can help in the early detection of AI outbreaks. The rRT-PCR assay can also be used to identify infections caused by H5 and H7 subtypes of AIV New isolates of AIV must be characterized as LPAI or HPAI for reporting and control purposes. The criteria for classification of an AI virus as HPAI are defined by the World Organization for Animal Health (OIE); the definition includes a virulence and a molecular criterion. The virulence requirement for HPAI is defined as an AIV killing 75% or more of eight inoculated chickens within 10 days. The molecular criterion is the presence of multiple dibasic amino acids at the proteolytic cleavage site of the haemagglutinin (H) protein. All HPAI viruses isolated before 2002 fulfilled both the virulence and molecular criteria. Consequently, nucleotide sequencing of the H gene and deduction of the amino acid motif at the H cleavage site has been successfully used to assess the virulence of H5 and H7 AIVs rapidly. Since 2002, however, there have been three outbreaks of HPAI where the viruses responsible for the outbreaks have either fulfilled the virulence criterion or the molecular criterion, but not both.

Amino Acid Sequence↗
PubMed2005

Multistate outbreak of Listeria monocytogenes infection linked to delicatessen turkey meat.

BACKGROUND: Despite a decreasing incidence of listeriosis in the United States, molecular subtyping has increased the number of recognized outbreaks. In September 2000, the New York City Department of Health identified a cluster of infections caused by Listeria monocytogenes isolates with identical molecular subtypes by pulsed-field gel electrophoresis (PFGE) and ribotyping. METHODS: To determine the magnitude of the outbreak and identify risk factors for infection, we notified state health departments and conducted a case-control study. A case was defined as a patient or mother-infant pair infected with Listeria monocytogenes whose isolate yielded the outbreak PFGE pattern. Controls were patients infected with Listeria monocytogenes whose isolate yielded a different PFGE pattern. Patients were asked about food and drink consumed during the 30 days before the onset of illness. RESULTS: Between May and December 2000, there were 30 clinical isolates of Listeria monocytogenes with identical PFGE patterns identified in 11 US states. Cases of infection caused by these isolates were associated with 4 deaths and 3 miscarriages. A case-control study implicated sliced processed turkey from a delicatessen (Mantel-Haenszel odds ratio, 8.0; 95% confidence interval, 1.2-43.3). A traceback investigation identified a single processing plant as the likely source of the outbreak, and the company voluntarily recalled 16 million pounds of processed meat. The same plant had been identified in a Listeria contamination event that had occurred more than a decade previously. CONCLUSIONS: Prevention of persistent L. monocytogenes contamination in food processing plants presents a critical challenge to food safety professionals.

Adult↗
PubMed2006

Rapid laboratory detection of meningococcal disease outbreaks caused by serogroup C Neisseria meningitidis.

Molecular subtyping is of significant importance to the recognition of outbreaks of meningococcal disease caused by serogroup C Neisseria meningitidis. We describe the application of multilocus variable number tandem repeat analysis (MLVA) for the molecular subtyping of N. meningitidis and compare its performance to that of pulsed-field gel electrophoresis (PFGE). For MLVA, a multiplex PCR assay targeting five variable number tandem repeat regions was developed and evaluated using a panel of sporadic and outbreak-associated serogroup C N. meningitidis isolates. MLVA was highly reproducible and provided results within 6 h. Overall, the discriminatory power of MLVA was equivalent to that of PFGE. The utilization of MLVA for subtyping N. meningitidis isolates provides a rapid and safer alternative to PFGE for identifying outbreaks of meningococcal disease. As such, it may provide public health officials with timely information that may minimize the spread of outbreak-related cases through prophylaxis.

Cluster Analysis↗
PubMed2026

Construction and validation of a &#x3b2;-hydroxybutyrylation-related molecular model for predicting prognosis of papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) usually has a favorable prognosis, yet a subset of patients develops persistent, recurrent, or biologically aggressive disease. The clinical relevance of lysine &#x3b2;-hydroxybutyrylation (Kbhb)-related transcriptional programs in PTC remains unclear. Accordingly, this study aimed to characterize Kbhb-related molecular heterogeneity in PTC, construct a prognostic signature, and explore its association with the tumor microenvironment (TME). METHODS: Transcriptomic and clinical data from PTC samples within The Cancer Genome Atlas Thyroid Carcinoma (TCGA-THCA) cohort were analyzed to identify Kbhb-related differentially expressed genes (DEGs), define molecular subtypes, construct a prognostic signature, and characterize tumor microenvironmental features. Single-cell RNA-sequencing data from PTC were further used to explore the cellular distribution of representative genes. RESULTS: We identified 51 Kbhb-related DEGs in PTC and defined two Kbhb molecular subtypes. The Kbhb_C2 subtype showed shorter progression-free interval (PFI) and a more immune- and stroma-enriched microenvironment. A six-gene prognostic signature comprising TARID, CDSN, PIMREG, KLRC1, SYT13, and NPR3 was then established. High-risk patients had significantly worse PFI in the full, training, and testing cohorts, with 1-, 3-, and 5-year areas under the curve (AUCs) of 0.715, 0.793, and 0.771, respectively, in the full cohort. High-risk tumors also exhibited higher stromal, immune, and ESTIMATE scores, altered immune infiltration, and increased expression of multiple immune checkpoint molecules. Single-cell analysis confirmed distinct cell-type-specific expression patterns of representative genes. CONCLUSIONS: Kbhb-related transcriptional programs define clinically relevant molecular heterogeneity in PTC and are closely associated with prognosis and TME remodeling. The identified six-gene signature provides a biologically interpretable framework for risk stratification in PTC.

Papillary thyroid carcinoma (PTC)↗
PubMed1998

Comparative incidence of the rearrangements of TEL/AML1 and ALL1 genes in pediatric precursor B acute lymphoblastic leukemias in India.

The TEL/AML1 translocation, which is specific for pre B-cell leukemias is predictive of a favorable treatment outcome. In contrast, translocations involving the ALL1 locus which are associated with both B and non B leukemias predict a poor outcome. To determine the relative distribution of high and low risk molecular subtypes of ALL in India, we analyzed the relative frequencies of these two translocations. The study included a random selection of 46 newly diagnosed patients of childhood ALL from the Tata Memorial Hospital, Bombay, India. Similar to the frequency observed in other world regions, we found an All1 rearrangement in less than 7% (3/46) of pre B-ALL patients. In contrast to the 25% frequency reported for other regions the low risk molecular subtype characterized by the TEL/AML1 translocation represented a comparatively smaller fraction (4/46) in this study. These results provide a preliminary support for a lower frequency of molecular subgroup of leukemias with a potential for favorable clinical outcome in precursor B-ALL from India.

Adolescent↗
PubMed2005

Oligodendroglioma: clinical study and survival analysis correlated with chromosomal anomalies.

OBJECT: Demonstration of the loss of chromosomes 1p and 19q in the presence of a brain neoplasm marks the emergence of genotype as a prognostic indicator. The authors report gene expression data for oligodendroglioma and correlate genotype with response to therapy. Gene expression subgroups may represent distinct types of disease. METHODS: Eighty-seven cases of supratentorial oligodendroglioma were selected from 145 cases treated in a single center between January 1990 and December 2001. Fluorescence in situ hybridization was used to determine the status of chromosomes 1p and 19q. Parameters evaluated included clinical data and radiological and histological features. Univariate and multivariate analyses were performed and a probability value less than 0.05 was considered significant. The patients included 48 women and 39 men. The overall mean age at presentation was 45 years for women and 36 years for men (p = 0.006). The univariate analysis identified the following as favorable prognostic factors: younger patient age (p = 10(-5)), female sex (p = 0.0025), seizure as a presenting symptom (p = 10(-5)), normal clinical examination (p = 10(-5)), absence of lesion enhancement on neuroimaging studies (p = 0.0231), lack of histological necrosis (p = 0.0003), absence of mitoses (p = 0.0014), 1p and 19q deletions (p = 0.0001), absence of recurrence (p = 0.0021), and adjuvant radiotherapy and/or chemotherapy (p = 10(-5)). The multivariate analysis identified patient age (p = 10(-5)) and chromosomal anomalies (p = 0.002) as independently linked to survival. Three molecular subtypes emerged: oligodendroglioma with 1p and 19q deletions, oligodendroglioma demonstrating polysomia and a lack of meaningful response to radiotherapy or chemotherapy, and oligodendroglioma with no 1p-9q deletion in which partial response was seen. CONCLUSIONS: According to our data, oligodendrogliomas could be divided into three molecular subtypes. Although chemotherapy seems efficient for managing this tumor, additional studies should be conducted to compare the efficacy of radiotherapy and chemotherapy.

Adolescent↗
PubMed2001

Cluster of serogroup C meningococcal disease associated with attendance at a party.

BACKGROUND: An unexplained increase has occurred in the incidence of invasive meningococcal disease in adolescents and young adults. METHODS: We investigated a cluster of serogroup C meningococcal disease in 3 previously healthy young adults who had attended a party in Maryland. Molecular subtyping was done on the isolates from the 3 cluster cases and 4 control isolates by pulsed-field gel electrophoresis (PFGE). The only common exposure was attendance at the party, where a large number of people reportedly smoked tobacco or marijuana and/or drank alcohol. RESULTS: The PFGE analysis of the 3 case isolates showed identical molecular subtypes. CONCLUSION: This investigation strongly suggests that transmission of the cluster strain occurred at the party. Transmission may have occurred in part as a result of the recently described risk factors of binge drinking and smoking. Taken together, these findings suggest that some of the recent increase in invasive meningococcal disease may be due to modifiable risk factors.

Adult↗
PubMed1989

Unexpected heterogeneity of BCR-ABL fusion mRNA detected by polymerase chain reaction in Philadelphia chromosome-positive acute lymphoblastic leukemia.

The Philadelphia (Ph1) chromosome results in a fusion of portions of the BCR gene from chromosome 22 and the ABL gene from chromosome 9, producing a chimeric BCR-ABL mRNA and protein. In lymphoblastic leukemias, there are two molecular subtypes of the Ph1 chromosome, one with a rearrangement of the breakpoint cluster region (bcr) of the BCR gene, producing the same 8.5-kilobase BCR-ABL fusion mRNA seen in chronic myelogenous leukemia (CML), and the other, without a bcr rearrangement, producing a 7.0-kilobase BCR-ABL fusion mRNA that is seen only in acute lymphoblastic leukemia (ALL). We studied the molecular subtype of the Ph1 chromosome in 11 cases of Ph1-positive ALL, including 2 with a previous diagnosis of CML, using a sensitive method to analyze the mRNA species based on the polymerase chain reaction (PCR). We observed unexpected heterogeneity in BCR-ABL mRNA in this population; in particular, 1 of 6 bcr-rearranged cases and 1 of 5 bcr-unrearranged cases contained none of the known fusion mRNA species, while 1 of the bcr-rearranged cases contained both. This latter case is particularly interesting because it suggests that the acquisition of an additional BCR-ABL fusion species may be a mechanism of disease progression. We conclude that the PCR gives additional information about the Ph1 chromosome gene products that cannot be obtained by genomic analysis, but that it cannot be used as the sole means of detection of this chromosomal abnormality in ALL because of the high incidence of false negative results.

Blotting, Southern↗
PubMed2026

RAG-mediated structural variation and its impact on relapse risk in acute lymphoblastic leukemia.

Relapse during treatment of B-cell acute lymphoblastic leukemia (B-ALL) is a harbinger of poor outcomes. Identifying biomarkers for subsequent relapse risk which are detectable at B-ALL diagnosis remains a priority. Off-target recombination-activating gene (RAG)-mediated structural variants (SVs) generate genomic instability that drives leukemogenesis and may underlie treatment resistance. Leveraging sequencing data in 1,496 pediatric B-ALL patients enriched for relapse status (relapse n=532; non-relapse n=964), we characterized RAG-mediated SVs across B-ALL molecular subtypes and examined their association with patient characteristics and their impact on clinical outcomes. Off-target RAG-mediated SVs were overall frequent, particularly in ETV6::RUNX1, ETV6::RUNX1-like, and Ph-like B-ALL subtypes, while increasing age-at-diagnosis was positively associated with burden of off-target RAG-mediated SVs (P<.001). Off-target RAG-mediated SVs with a recombination signal sequence (RSS) at one breakpoint, a hallmark of off-target RAG activity, were significantly more frequent at diagnosis in patients who subsequently relapsed (P=.001). This association remained significant in multivariable regression analysis (per SV odds ratio [OR]:1.08, 95%CI:1.04-1.12), in minimal residual disease (MRD)-negative patients (OR:1.09, 95%CI:1.04-1.14) and across subtypes. Excluding deletions, MRD-negative ETV6::RUNX1 patients with &#x2265;3 off-target RAG-mediated SVs had a >3-fold risk of relapse (hazard ratio:3.47, 95% CI:1.86-6.49). RAG-mediated SVs were also associated with relapse risk in T-cell ALL patients. Off-target RAG-mediated SV burden at diagnosis is a risk factor of relapse in pediatric ALL across molecular subtypes and independent of MRD status.

Journal Article↗
PubMed2000

Molecular epidemiology of diphtheria.

Molecular subtyping of Corynebacterium diphtheriae identified significant genetic diversity within the species and led to the identification of a unique clonal group that emerged in Russia in 1990 at the beginning of the current epidemic. Strains of this group belong to a distinct electrophoretic type complex and are of ribotypes D1 and D4. Identification of the group allowed for precise monitoring of the epidemic's progression and for rapid detection of cases imported to other countries. The evolution of this clonal group was monitored, and changes were identified. Molecular analysis revealed that no amino acid substitutions have occurred in the diphtheria toxin gene of the epidemic clone strains, reaffirming the use of the current vaccine as the single most effective preventive measure. Application of molecular subtyping methods and continuous monitoring of the spread of these clones has made it possible to distinguish rapidly between epidemic, endemic, and imported cases, allowing for implementation of timely and adequate preventive measures and providing reassurance that no secondary spread resulted from importations.

Bacterial Typing Techniques↗
PubMed1990

Molecular methods to detect the Philadelphia chromosome.

The Ph1 chromosome has two molecular subtypes: a bcr-positive seen in CML and some cases of ALL, and the bcr-negative subtype mainly seen in ALL. In CML, because of the restriction of chromosome 22 breakpoints to the bcr, Southern analysis to detect bcr rearrangements also can be used to detect the Ph1 chromosome. In contrast, the translocation breakpoints on the Ph1 chromosome are scattered in ALL, so that other methods such as PFGE and PCR are necessary to detect the Ph1 chromosome. In both CML and ALL, use of these methods to detect molecular abnormalities may be superior to cytogenetics in detecting chromosomal abnormalities. Southern analysis also can be used in CML to map breakpoint locations within the bcr. This may offer prognostic information as to the length of chronic phase, but there is conflicting information as to the validity of this approach. The modified PCR (using cDNA from mRNA) can be used to detect the Ph1 chromosome and to define which of the molecular subtypes are present. The exquisite sensitivity of this method, which is capable of detecting as little as a single abnormal molecule of RNA or DNA, makes it suited for the detection of minimal residual disease in both CML and ALL. This is particularly useful after intensive therapies, such as bone marrow transplantation. Whether these low levels of fusion gene expression are of prognostic significance is still unclear.

Genetic Techniques↗