Biomedical subjects

Gordon W Dewald

Publications and source records attributed to Gordon W Dewald.

At least 19 recordsLinked to original sources

PubMed2006

Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial.

Pretreatment cytogenetics is a known predictor of outcome in hematologic malignancies. However, its usefulness in adult acute lymphoblastic leukemia (ALL) is generally limited to the presence of the Philadelphia (Ph) chromosome because of the low incidence of other recurrent abnormalities. We present centrally reviewed cytogenetic data from 1522 adult patients enrolled on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. The incidence and clinical associations for more than 20 specific chromosomal abnormalities are presented. Patients with a Ph chromosome, t(4;11)(q21;q23), t(8;14)(q24.1;q32), complex karyotype (5 or more chromosomal abnormalities), or low hypodiploidy/near triploidy (Ho-Tr) all had inferior rates of event-free and overall survival when compared with other patients. In contrast, patients with high hyperdiploidy or a del(9p) had a significantly improved outcome. Multivariate analysis demonstrated that the prognostic relevance of t(8;14), complex karyotype, and Ho-Tr was independent of sex, age, white cell count, and T-cell status among Ph-negative patients. The observation that Ho-Tr and, for the first time, karyotype complexity confer an increased risk of treatment failure demonstrates that cytogenetic subgroups other than the Ph chromosome can and should be used to risk stratify adults with ALL in future trials.

Adult↗

PubMed2006

Efficacy of conventional cytogenetics and FISH for EGR1 to detect deletion 5q in hematological disorders and to assess response to treatment with Lenalidomide.

In clinical practice, whether FISH for EGR1 in interphase nuclei has similar efficacy to detect deletion 5q anomalies as conventional cytogenetic studies is unknown. We compared conventional cytogenetics and FISH for 145 patients with deletion 5q and detected this anomaly by both methods in 144. Nine patients with myelodysplasia were studied before and after treatment with Lenalidomide and results were concordant for 28 of 29 specimens. FISH did not detect anomalies other than deletion 5q in 31 patients. This study suggests FISH is useful to detect deletion 5q, but is not a substitute for conventional cytogenetics.

Adult↗

PubMed2006

Prospective evaluation of clonal evolution during long-term follow-up of patients with untreated early-stage chronic lymphocytic leukemia.

PURPOSE: Retrospective studies suggest cytogenetic abnormalities detected by interphase fluorescent in situ hybridization (FISH) can identify patients with chronic lymphocytic leukemia (CLL) who will experience a more aggressive disease course. Other studies suggest that patients may acquire chromosome abnormalities during the course of their disease. There are minimal prospective data on the clinical utility of the widely used hierarchical FISH prognostic categories in patients with newly diagnosed early-stage CLL or the frequency of clonal evolution as determined by interphase FISH. PATIENTS AND METHODS: Between 1994 and 2002, we enrolled 159 patients with previously untreated CLL (83% Rai stage 0/I) on a prospective trial evaluating clonal evolution by FISH. Patients provided baseline and follow-up specimens for FISH testing during 2 to 12 years. RESULTS: Chromosomal abnormalities detected by FISH at study entry predicted overall survival. Eighteen patients experienced clonal evolution during follow-up. The rate of clonal evolution increased with duration of follow-up with only one occurrence in the first 2 years (n = 71; 1.4%) but 17 occurrences (n = 63; 27%) among patients tested after 5+ years. Clonal evolution occurred among 10% of ZAP-70-negative and 42% of ZAP-70-positive patients at 5+ years (P = .008). CONCLUSION: This clinical trial confirms prospectively that cytogenetic abnormalities detected by FISH can predict overall survival for CLL patients at the time of diagnosis, but also suggests that many patients acquire new abnormalities during the course of their disease. Patients with higher ZAP-70 expression may be more likely to experience such clonal evolution. These findings have important implications for both clinical management and trials of early treatment for patients with high-risk, early-stage CLL.

Adult↗

PubMed2006

Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia.

Building on the prior work of use of pentostatin in chronic lymphocytic leukemia (CLL), we initiated a trial of combined pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2), and rituximab (375 mg/m2) for 65 symptomatic, previously untreated patients. Of 64 evaluable patients, 34 (53%) were high Rai risk, 71% were nonmutated for the immunoglobulin heavy-chain variable region gene, 34% were CD38+, and 34% were ZAP-70+. Thirty patients (52%) had one anomaly detected by fluorescence in situ (FISH) hybridization, and 21 (36%) had complex FISH defects. Thirty-eight patients (58%) had grade 3+ hematologic toxicity but minimal transfusion needs and no major infections. Responses occurred in 58 patients (91%), with 26 (41%) complete responses (CRs), 14 (22%) nodular partial responses (nodular PRs), and 18 (28%) partial responses (PRs). Many patients with a CR also lacked evidence of minimal residual disease by 2-color flow cytometry. Examination of prognostic factors demonstrated poor response in the 3 patients with del(17p). In contrast, we found this regimen was equally effective in young versus older (>70 years) patients and in del(11q22.3) versus other favorable prognostic factors. Thus, this novel regimen of pentostatin, cyclophosphamide, and rituximab for previously untreated patients with CLL demonstrated significant clinical activity despite poor risk-based prognoses, achievement of minimal residual disease in some, and modest toxicity.

Adult↗

PubMed2006

Utility of interphase FISH to stratify patients into cytogenetic risk categories at diagnosis of AML in an Eastern Cooperative Oncology Group (ECOG) clinical trial (E1900).

We evaluated the efficacy of FISH to detect chromosome anomalies in the evaluation of young (<60 years) patients with AML. Patients were enrolled in E1900, an ECOG clinical trial for AML. The protocol was designed to collect bone marrow or blood for both cytogenetic and FISH studies at study entry (diagnosis). FISH for each patient was performed and utilized eight probe sets to detect t(8;21), t(9;22), t(11;var), t(15;17), inv(16), +8, -5/5q, and -7/7q. We analyzed 237 specimens with complete cytogenetic and FISH results. Results for each specimen were classified by probe set into one of six categories. The concordance rate between cytogenetic and FISH results ranged from 98 to 100% for all probe sets and kappa analysis for concordance had a p-value of <0.0001. The high level of agreement between cytogenetic and FISH results demonstrate the accuracy of a panel of eight FISH probe sets for the detection of significant abnormalities in AML. Data from this investigation support the use of FISH as an adjunct method to increase the yield of useful cytogenetic results in large cooperative trials and demonstrate the potential of FISH as a follow-up study of minimal residual disease in ECOG trials.

Acute Disease↗

PubMed2006

The clinical spectrum of adult acute myeloid leukaemia associated with core binding factor translocations.

To better understand the spectrum of adult acute myeloid leukaemia (AML) associated with core binding factor (CBF) translocations, 370 patients with newly diagnosed CBF-associated AML were analysed. Patients' age ranged from 16-83 years (median 39 years) with a slight male predominance (55%); 53% had inv(16); 47% had t(8;21). Patients with t(8;21) tended to be younger (P = 0.056), have lower peripheral blood white cell counts (P < 0.0001) and were more likely to have additional cytogenetic abnormalities (P < 0.0001). Loss of sex chromosome, del(9q) and complex abnormalities were more common among patients with t(8;21), while +22 and +21 were more common with inv(16). Overall, 87% [95% confidence interval (CI) 83-90%] of patients achieved complete response (CR) with no difference between t(8;21) and inv(16); however, the CR rate was lower in older patients due to increased resistant disease and early deaths. Ten-year overall survival (OS) was 44% (95% CI 39-50%) and, in multivariate analysis, was shorter with increasing age (P < 0.0001), increased peripheral blast percentage (P = 0.0006), in patients with complex cytogenetic abnormalities in addition to the CBF translocation (P = 0.021), and in patients with t(8;21) (P = 0.025). OS was superior in patients who received regimens with high-dose cytarabine, a combination of fludarabine and intermediate-dose cytarabine, or haematopoietic cell transplantation.

Acute Disease↗

PubMed2006

A phase II trial of arsenic trioxide for relapsed and refractory acute lymphoblastic leukemia.

We designed a phase II trial of arsenic trioxide (AT) for the treatment of relapsed and refractory acute lymphoblastic leukemia (ALL). The dose administered was 0.25 mg/kg/day intravenously for 5-7 days per week for up to 60 days. Of 11 patients eligible, eight had B-cell and three T-cell ALL and two were Philadelphia chromosome-positive. The median duration of therapy was 21 days (range 7-28). One patient died of an infection. There were no responses. Ten patients have died. The median survival was 3.2 months (range 1.2-4.1). We conclude that AT is not active in the treatment of ALL.

Antineoplastic Agents↗

PubMed2006

Presence of unfavorable cytogenetic abnormalities is the strongest predictor of poor survival in secondary myelofibrosis.

BACKGROUND: Postpolycythemic (PV) and postthrombocythemic (ET) myeloid metaplasia are consensually referred to as secondary myelofibrosis (sMF). Prognostic variables in sMF are not as well defined as they are for de novo myelofibrosis with myeloid metaplasia (MMM), which is also known as agnogenic myeloid metaplasia (AMM). Such information is particularly crucial for management decisions in transplant-eligible patients. METHODS: Diagnoses of PV and ET required fulfillment of the World Health Organization criteria for the diagnosis of MMM as well as an antecedent history of either polycythemia vera or essential thrombocythemia that was supported by bone marrow examination. Cytogenetic findings were classified as being either favorable (normal or isolated 13q- or 20q- clones) or unfavorable (presence of abnormalities other than 13q- and 20q-). RESULTS: The study population was comprised of 66 young patients (age <60 yrs) with sMF, including 37 patients with PV and 29 patients with ET. Multivariate analysis of parameters other than cytogenetics identified older age (P = .02), anemia (hemoglobin level <10 g/dL [P = .007]), and PV (P = .009) to be independent risk factors for shortened survival. However, when such analysis was restricted to patients in whom cytogenetic studies were performed (n = 31 patients), the presence of unfavorable cytogenetic abnormalities (i.e., clones other than 20q- and 13q-) became the only adverse prognostic factor for survival (P = .001). A similar analysis in a temporal cohort of 50 age-matched patients with AMM also identified unfavorable cytogenetics as an independent predictor of poor survival, along with thrombocytopenia and anemia. CONCLUSIONS: The results of the current study suggest that cytogenetic findings might supersede AMM-derived prognostic scoring systems for predicting survival in patients with sMF.

Adult↗

PubMed2006

Respective clustering of unfavorable and favorable cytogenetic clones in myelofibrosis with myeloid metaplasia with homozygosity for JAK2(V617F) and response to erythropoietin therapy.

BACKGROUND: Patients who have myelofibrosis with myeloid metaplasia (MMM) display recurrent, albeit nonspecific cytogenetic abnormalities that are diverse prognostically. For the current study, the authors explored the relation between specific cytogenetic clones and JAK2(V617F) mutational status in patients with MMM and the effects on treatment response to erythropoietin (Epo). METHODS: Concomitantly collected blood granulocytes and bone marrow were processed for JAK2(V617F) mutation analysis and cytogenetic studies, respectively. Genomic DNA was amplified by polymerase chain reaction, and fluorescent dye chemistry sequencing was performed by using the same primers that were used for amplification. RESULTS: Among 105 study patients, cytogenetic abnormalities were detected in 47 patients (45%), and the JAK2(V617F) mutation was detected in 52 patients (50%). Comparison of mutational frequencies between favorable (normal, sole 13q-, or 20q- clones; n = 70 patients) and unfavorable (all other abnormalities; n = 35 patients) cytogenetic categories revealed a significantly different incidence of homozygous JAK2(V617F) between them (9% vs. 23%, respectively; P = .04). Furthermore, the mutant allele coexisted with several recurrent cytogenetic lesions. Among 25 patients who received Epo either alone (n = 17 patients) or in combination with hydroxyurea (n = 8 patients), 4 patients (16%) achieved a response, and none of them were homozygous for JAK2(V617F). Conversely, a response was more likely (P = .0001) in the presence of favorable cytogenetic abnormalities (i.e., 3 of 4 responders carried sole 13q- or 20q- clones). CONCLUSIONS: Unfavorable and favorable cytogenetic clones in MMM clustered with homozygosity for JAK2(V617F) and treatment response to Epo-based therapy, respectively.

Clone Cells↗

PubMed2006

Metaphase cells with normal G-bands have cryptic interstitial deletions in 13q14 detectable by fluorescence in situ hybridization in B-cell chronic lymphocytic leukemia.

Interphase fluorescence in situ hybridization (FISH) studies with D13S319 show that deletions of 13q14 are common in B-cell chronic lymphocytic leukemia (B-CLL). In contrast, conventional cytogenetic studies in B-CLL seldom reveal abnormalities of chromosome 13. We hypothesized that chromosome 13 anomalies might not be detected because they are caused by cryptic deletions rather than by the absence of dividing B-CLL cells. To investigate this possibility, we used FISH with D13S319 to study metaphases from 12 patients known to have 13q- by interphase FISH. These same patients had normal chromosomes by conventional cytogenetic studies. As a result of this study, we report evidence that B-CLL metaphases with 13q- are not detected because these deletions are often cryptic and not visible by standard G-banding.

Aged↗

PubMed2006

Loss of TP53 is due to rearrangements involving chromosome region 17p10 approximately p12 in chronic lymphocytic leukemia.

Loss of tumor protein 53 (TP53) has been associated with aggressive disease and poor response to therapy in B-cell chronic lymphocytic leukemia (B-CLL). TP53 is located at chromosome band 17p13 and its absence can be detected by fluorescence in situ hybridization (FISH) in the interphase nuclei of 8-10% patients with B-CLL. To study the cytogenetic mechanism for loss of TP53, metaphase and interphase FISH studies were conducted on 16 B-CLL patients to investigate 17p10 to 17p12, a chromosome region known to be rich in low-copy DNA repeats. Loss of TP53 was caused by an isochromosome with breakpoints between 17p10 and 17p11.2 in four patients, an unbalanced translocation involving 17p10 to 17p11.2 in nine patients, and an unbalanced translocation involving 17p11.2 to 17p12 in three patients. These findings indicate that loss of TP53 results from the absence of nearly the entire chromosome 17 p-arm rather than to monosomy 17 or deletions of TP53. Translocations or isochromosome formations at sites of low-copy DNA repeats in 17p10 to 17p12 appear to be the mechanism for the loss of TP53 in B-CLL.

Aged↗

PubMed2006

Preclinical validation of fluorescence in situ hybridization assays for clinical practice.

PURPOSE: Validation of fluorescence in situ hybridization assays is required before using them in clinical practice. Yet, there are few published examples that describe the validation process, leading to inconsistent and sometimes inadequate validation practices. The purpose of this article is to describe a broadly applicable preclinical validation process. METHODS: Validation is performed using four consecutive experiments. The Familiarization experiment tests probe performance on metaphase cells to measure analytic sensitivity and specificity for normal blood specimens. The Pilot Study tests a variety of normal and abnormal specimens, using the intended tissue type, to set a preliminary normal cutoff and establish the analytic sensitivity. The Clinical Evaluation experiment tests these parameters in a series of normal and abnormal specimens to simulate clinical practice, establish the normal cutoff and abnormal reference ranges, and finalize the standard operating procedure. The Precision experiment measures the reproducibility of the new assay over 10 consecutive working days. To illustrate documentation and analysis of data with this process, the results for a new assay to detect fusion of IGH and BCL3 associated with t(14;19)(q32;q13.3) in lymphoproliferative disorders are provided in this report. RESULTS: These four experiments determine the analytic sensitivity and specificity, normal values, precision, and reportable reference ranges for validation of the new test. CONCLUSION: This report describes a method for preclinical validation of fluorescence in situ hybridization studies of metaphase cells and interphase nuclei using commercial or home brew probes.

B-Cell Lymphoma 3 Protein↗

PubMed2006

The incidence and anatomic site specificity of chromosomal translocations in primary extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) in North America.

Several balanced translocations have been identified in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) but there are few data regarding their frequency in different anatomic sites or the frequency of translocations involving BCL6 or kappa or lambda immunoglobulin light chain genes (IGK or IGL), particularly in patients from geographic regions other than Europe and Japan. One hundred thirty-three paraffin-embedded North American primary MALT lymphoma specimens from diverse anatomic sites were studied by fluorescence in situ hybridization (FISH) using probes for API2-MALT1, IGH-MALT1, IGH-BCL10, IGH-FOXP1, IGH, +/- centromeres 3, 7, 12, and 18, and a subset (n=74) were analyzed using FISH probes for IGK, IGL, and BCL6. Translocations were mutually exclusive and were detected in 26% of cases (17% API2-MALT1, 5% IGH-MALT1, 3% IGH-unknown translocation partner, and 1% IGH-BCL10). Aneuploidy was associated with IGH-MALT1 and IGH-BCL10 but only rarely with API2-MALT1. There was striking site specificity, with API2-MALT1 showing a marked predilection for lung and intestine, and IGH-MALT1 and IGH-BCL10 occurring almost exclusively in lung. Twenty-three percent of translocation-negative primary MALT lymphomas from diverse sites showed complete/partial trisomy 18. No MALT lymphomas with translocations involving IGK, IGL, BCL6, or FOXP1 were identified. This FISH panel detected cytogenetic abnormalities in half of all MALT lymphomas, and translocations arose preferentially in MALT lymphomas of the lung and gastrointestinal tract. Differences in incidence and anatomic site specificity of translocations between North American and non-North American cases may reflect geographic variability of infectious or other etiologic factors.

Adaptor Proteins, Signal Transducing↗

PubMed2006

HER-2 fluorescence in situ hybridization: results from the survey program of the College of American Pathologists.

CONTEXT: Fluorescence in situ hybridization (FISH) is a common method used to determine HER-2 status in breast cancer. Limited information is available concerning reproducibility of FISH in determining HER-2 gene amplification. OBJECTIVE: To present proficiency testing results of FISH for HER-2 conducted by the Cytogenetics Resource Committee of the College of American Pathologists/American College of Medical Genetics. DESIGN: During the past 5 years, unstained sections from 9 invasive breast carcinomas were used for HER-2 FISH proficiency testing, allowing for comparison of FISH results among a large number of laboratories. Additional data were collected using an educational (ungraded) challenge and supplemental questions in the surveys. RESULTS: The number of laboratories participating in HER-2 FISH proficiency testing has increased steadily during the past 5 years (from 35 in 2000 to 139 in 2004). Reproducibility of test results among laboratories was excellent for breast tumors with low copy number (no HER-2 amplification) and for breast tumors with high copy number (HER-2 amplification). However, there was considerable variation in interpretation of results for a tumor with low-level HER-2 amplification that was tested on 2 separate occasions. Responses to supplemental questions indicated that there was a need for consensus on the use of a separate equivocal/borderline interpretative category and the need for standardization of cutoff values used to define interpretative categories. CONCLUSIONS: The College of American Pathologists proficiency survey programs provide useful information concerning the reproducibility of clinical testing for HER-2 by FISH and reflect clinical interpretation of HER-2 FISH analyses from laboratories across the country.

Adenocarcinoma↗

PubMed2006

Cytogenetic heteromorphisms: survey results and reporting practices of giemsa-band regions that we have pondered for years.

CONTEXT: Cytogenetic heteromorphisms (normal variants) pose diagnostic dilemmas. Common Giemsa-band heteromorphisms are not described in the literature, although Giemsa-banding is the method most frequently used in cytogenetic laboratories. OBJECTIVE: To summarize the responses from more than 200 cytogeneticists concerning the definition and reporting of cytogenetic heteromorphisms, to offer these responses as a reference for use in clinical interpretations, and to provide guidance for interpretation of newly defined molecular cytogenetic heteromorphisms. DESIGN: The Cytogenetics Resource Committee of the College of American Pathologists and the American College of Medical Genetics administered a proficiency testing survey in 1997 to 226 participant cytogenetic laboratories. Supplemental questions asked whether participants considered particular Giemsa-banded chromosomal features to be heteromorphisms and if these would be described in a cytogenetic clinical report. RESULTS: Responses were obtained from 99% of participants; 61% stated they would include selected heteromorphism data in a clinical report. More than 90% considered prominent short arms, large or double satellites, or increased stalk length on acrocentric chromosomes to be heteromorphisms; 24% to 36% stated that they would include these in a clinical report. Heterochromatic regions on chromosomes 1, 9, 16, and Y were considered heteromorphisms by 97% of participants, and 24% indicated they would report these findings. Pericentric inversions of chromosomes 1, 2, 3, 5, 9, 10, 16, and Y were considered heteromorphisms with more than 75% of respondents indicating they would report these findings. CONCLUSIONS: Responses were not unanimous, but a clear consensus is presented describing which Giemsa-band regions were considered heteromorphisms and which would be reported.

Azure Stains↗

PubMed2005

Prognostic diversity among cytogenetic abnormalities in myelofibrosis with myeloid metaplasia.

BACKGROUND: Approximately 30-50% of patients with myelofibrosis with myeloid metaplasia (MMM) demonstrate detectable cytogenetic abnormalities, the prognostic value of which has not been completely defined by previous retrospective studies. The current prospective study addresses this issue in the context of currently accepted independent prognostic variables. METHODS: The current study is a single institution study in which patients with MMM were accrued between January 2000 and August 2001 and followed in a prospective fashion. All study patients underwent bone marrow examination with cytogenetic studies as well as comprehensive clinical and laboratory evaluation at the time of karyotype analysis. RESULTS: Among the study cohort of 81 patients (with a median age of 61 years; 54 males), the cytogenetic findings were normal in 44 patients (54%; Group 1). The remaining 37 patients (46%) demonstrated either interstitial deletions involving the long arm of chromosome 13 or 20 (9 patients; Group 2) or other abnormalities (28 patients; Group 3). All study patients were followed prospectively for a minimum of 40 months (range, 40-55 months). Survival from the time of karyotypic analysis was found to be similar between Groups 1 and 2 but was significantly worse in Group 3. Furthermore, none of the patients in Group 2 experienced leukemic transformation, whereas five patients each from the other two groups did. Multivariate analysis identified an unfavorable cytogenetic profile (Group 3), > or = 1% circulating blasts, a hemoglobin level of <10 g/dL, and constitutional symptoms as adverse prognostic features for overall survival. CONCLUSIONS: Specific cytogenetic lesions in patients with MMM might carry an independent prognostic effect for both survival and the risk of leukemic transformation. Such information should assist in decision making when considering aggressive treatment approaches.

Adult↗

PubMed2005

Relationship of patient survival and chromosome anomalies detected in metaphase and/or interphase cells at diagnosis of myeloma.

The clinical efficacy of evaluating genetic anomalies in metaphase cells versus interphase nuclei for multiple myeloma (MM) is poorly understood. Therefore, survival for 154 patients with newly diagnosed untreated MM was compared with results from analysis of metaphase and interphase cells. Metaphases were studied by conventional cytogenetics and fluorescent-labeled DNA probes (fluorescence in situ hybridization [FISH]), whereas inter-phase nuclei were evaluated only by FISH. All FISH studies were done using DNA probes to detect t(4;14)(p16;q32), t(11;14)(q13;q32), t(14;16)(q32;q23), del(17) (p13.1), and chromosome 13 anomalies. Metaphases were abnormal by cytogenetics and/or metaphase FISH in 61 (40%) patients. Abnormal interphase nuclei were observed in 133 (86%) patients, including each patient with abnormal metaphases. FISH was a necessary adjunct to cytogenetics to detect t(4;14) and t(14;16) in metaphase cells. Patient survival was especially poor for patients with greater than 50% abnormal interphase nuclei, although this result was more likely due to level of plasma cells than specific chromosome anomalies. For metaphase data, patients with t(4;14), t(14;16), del(17) (p13.1), and/or chromosome 13 anomalies (primarily monosomy 13) had poor survival. A different outcome was observed for interphase data as patients with t(4;14) or t(14;16) had poor survival, whereas patients with chromosome 13 anomalies had intermediate survival: interphase FISH did not substitute for metaphase analysis.

Adult↗

PubMed2005

The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and myelodysplastic syndromes.

A somatic mutation in the JH2 autoinhibitory domain of the Janus kinase 2 (JAK2) tyrosine kinase was recently described in polycythemia vera, essential thrombocythemia, and myelofibrosis with myeloid metaplasia. The prevalence of this mutation in either "atypical" myeloproliferative disorders (MPDs) or the myelodysplastic syndromes (MDSs) is unknown. Bone marrow-derived genomic DNA from 245 patients--119 with chronic myelomonocytic leukemia (CMML), 101 with MDS, 11 with hypereosinophilic syndrome (HES), 8 with systemic mastocytosis (SM), and 6 with chronic neutrophilic leukemia (CNL)--was screened for the JAK2 V617F mutation. A mutant allele was detected in 11 patients: 3 with CMML (3%), 5 with MDS (5%), 2 with SM, and 1 with CNL. Interestingly, one of the patients with SM and the patient with CNL with JAK2 V617F had a history of lymphoma, and this patient with SM also had associated myelofibrosis and CMML. The current observation strengthens the specific association between JAK2 V617F and classic MPD, but also suggests an infrequent occurrence in other myeloid disorders.

Adult↗