Neutrophilic‐chronic myeloid leukemia

Abstract

BACKGROUNDNeutrophilic‐chronic myeloid leukemia (CML‐N) has been described as a CML variant associated both with a distinctive molecular defect of the Philadelphia chromosome and with a more benign clinical course than classic CML. The translocation (9;22) in CML‐N results in the transcription of an e19/a2 type BCR/ABL mRNA that codes for a 230‐kD BCR/ABL protein (p230). The indolence of the clinical course of patients with CML‐N has been disputed.METHODSThe objectives of this study were to quantify and correlate with clinical outcome the p230 mRNA and protein in patients with CML‐N, to describe six new patients and the follow‐up (with molecular analysis) of five previously reported patients with CML‐N, and to review characteristics of all patients with CML‐N and p230 BCR/ABL reported to date in the literature.RESULTSQuantitative polymerase chain reaction assays on specimens from the great majority of patients with CML‐N revealed minimal numbers of molecules of p230 BCR/ABL transcripts per total RNA. This also was associated with a lack of detectable p230 BCR/ABL protein in patient specimens, even in one patient who was followed for 16 years after diagnosis. This may explain the milder leukemic phenotype in most patients with CML‐N. A review of all 23 patients who had an e19/a2 type BCR/ABL translocation suggested that the low level of p230 BCR/ABL mRNA and the lack of detectable p230 BCR/ABL protein in patients with no additional cytogenetic abnormalities may predict their indolent clinical course.CONCLUSIONSPatients with p230 positive CML‐N have indolent course, probably as a result of low p230 mRNA and protein levels. This supports the need to conduct additional molecular studies, even if cytogenetic studies have revealed t(9;22), because of the prognostic importance of the molecular findings. Cancer 2002;94:2416–25. © 2002 American Cancer Society.DOI 10.1002/cncr.10490

Cytogenetic and Molecular Genetic Aspects of Chronic Myeloid Leukaemia

“…Support for this hypothesis comes from a recent report in which the number of e19a2 mRNA transcripts was determined by real-time quantitative PCR (RQ-PCR) in seven patients diagnosed with CML-N [106]. Minimal amounts of e19a2 mRNA were detected in the majority of these patients, suggesting that transcription from BCR-ABL fusion genes with e19a2 junctions occurs frequently at an extremely low level.…”

“…Moreover, there are currently no known genetic or biological markers that are specific for ET and the diagnostic criteria for this disease specifically exclude patients with a Ph chromosome or a BCR-ABL fusion gene [105]. Although very high platelet counts do seem to be associated with expression of p230 Bcr-Abl in some cases of N-CML, in the most recent survey of the literature [106], only five out of twenty-four patients with e19a2 transcripts were found to have excessive platelet counts (>1,000 × 10 9 /l).…”

“…Minimal amounts of e19a2 mRNA were detected in the majority of these patients, suggesting that transcription from BCR-ABL fusion genes with e19a2 junctions occurs frequently at an extremely low level. Interestingly, the p230 Bcr-Abl protein is consistently undetectable by immunoblotting [106]and in the only case in which the protein has been detected, the patient exhibited duplication of the Ph chromosome [108]. Transcription may be subject to silencing because of the presence of at least three transcriptional repressor sequences within the intron downstream of BCR exon e14 [109].…”

Transgenic Mouse Models of BCR/ABL-Positive Chronic Myelogenous Leukemia: A Review

“…The findings of marked splenic megakaryocytosis and peripheral blood thrombocytosis in the P230 BCR/ABL transgenic mice are frequently seen in human CML, Phpositive CNL and Ph-positive essential thrombocythemia (ET) [36]. These disease findings in the P210 and the P230 BCR/ABL transgenic mice might have been due to the respective structures of the b3a2-type p210 BCR/ABL cDNA and p230 BCR/ABL cDNA.…”

“…Patients having P230 BCR/ABL had the two disease phenotype of Ph-positive ET or chronic neutrophilic leukemia (CNL) [36,39,40]. The disease phenotypes of ET and CNL are possibly a result of the expression level of the P230BCR/ABL protein.…”