0165-4608/00/$–see front matter PII S0165-4608(99)00168-5 Cancer Genet Cytogenet 118:14–19 (2000)  Elsevier Science Inc., 2000. All rights reserved. 655 Avenue of the Americas, New York, NY 10010 Silent Philadelphia Chromosome: A Distinct Developmental Stage in a Philadelphia Chromosome-Positive Chronic Myeloproliferation? László Pajor, János A. Vass, László Kereskai, Károly Szuhai, Lenke Molnár, and Pál Jáksó ABSTRACT: In this paper, a patient is described who presented with peripheral blood and bone mar- row features uncharacteristic of chronic granulocytic leukemia, which proved to be Philadelphia (Ph) chromosome-positive by metaphase and interphase cytogenetic analyses but lacked the p210 type of BCR/ABL fusion gene mRNA product by two different sensitive RT-PCR assays. In the course of the 32- month follow-up with a termination into a myeloblastic crisis, molecular investigations were per- formed four times. They indicated a constantly high rate of Ph positive cells and lack of BCR/ABL mRNA expression, except in the second investigation, when the patient showed reverse transcrip- tion polymerase chain reaction positivity with b3/a2 type of chimera, fusion gene mRNA expres- sion, and a striking change in the bone marrow histology. Our findings might indicate that the dor- mant Ph chromosome state may exist not only at the primitive progenitor, but also at the entire peripheral blood cell compartment level. © Elsevier Science Inc., 2000. All rights reserved. INTRODUCTION A balanced translocation between chromosomes 9 and 22, resulting in a minute chromosome, the Philadelphia chro- mosome (Ph), is highly characteristic of human chronic granulocytic leukemia (CGL), which is a clonal disorder of stem cell origin [1, 2]. The resulting chimera gene ex- presses a novel 8.2 kilobase (kb) bcr-abl mRNA encoding for the p210 with acquired tyrosine kinase activity [3, 4]. Cellular elements of the hemopoietic compartment in the Ph-positive CGL patients seems to be heterogeneous in term of both the Ph positivity and BCR-ABL mRNA expression [5]. Not only the Ph and BCR-ABL mRNA-neg- ative compartment as representative of the residual he- mopoiesis exists, but a various amount of hemopoietic colonies as well as phenotypically defined immature elements may exhibit the Ph-positive but BCR-ABL mRNA-negative geno- and phenotype [6–10]. The signifi- cance of this dormant state is unknown, but it obviously poses particular difficulties for monitoring therapy and the post-transplant state, as well as the selection of cellu- lar compartments suitable for autologous transplantation on the basis of chimera mRNA expression by polymerase chain reaction (PCR). Here we describe a patient with clinical and laboratory findings uncharacteristic of CGL at the onset of the dis- ease who, however, proved to be Ph and BCR/ABL rear- rangement positive by meta- and interphase cytogenetic analyses, but BCR-ABL mRNA remained undetectable by sensitive nested reverse transcription PCR (RT-PCR) tech- niques. At a constantly high rate of Ph-positive blood cells, the patient’s blood sample turned, over time, into p210 mRNA-positive, which was accompanied with a change of the bone marrow histology. MATERIALS AND METHODS Patient History A 55-year-old white male was admitted to the hospital be- cause of upper abdominal pain, fatigue, dizziness, and melena. Investigations revealed a marked hepatosplenom- egaly, thrombocytosis, and leukocytosis. Based on the his- tology, cytology, and cytochemistry of the peripheral blood and bone marrow aspirate, as well as on the mo- lecular findings, a chronic myeloproliferative disorder (CMPD) of Ph-positive CGL-type with atypical features was reported. During the course of the 32-month follow- up, hydroxyurea was administered because of interferon- From the Department of Pathology (L. P., J. A. V., L. K., K. S., P. J.), 1st Department of Internal Medicine (L. M.), and the Uni- versity Medical School of Pécs, Pécs, Hungary. Address reprint requests to: László Pajor, M.D., Ph.D., Depart- ment of Pathology, University Medical School of Pécs, 12 Szigeti Str. PO Box 99, H-7643 Pécs, Hungary. Received February 15, 1999; accepted July 27, 1999.