TRISOMY 8 IN PDGFRB-NEGATIVE CELLS IN A PATIENT WITH IMATINIB SENSITIVE CHRONIC MYELOMONOCYTIC LEUKAEMIA AND THE T(5;16)(Q33;P13)/PDGFRB/NDE1 FUSION

Background. The development of clonal chromosome abnormalities in Philadelphia-chromosome negative cells was well documented in chronic myeloid leukaemia (CML) responding to interferon-a (IFN) and imatinib (IM). Fusion genes involving the platelet-derived growth factor receptor b (PDGFRB) were identified in Ph-negative chronic myeloproliferative disorders (CMPD) generating a constitutive tyrosine kinase activity usually sensitive to IM. We identified a novel PDGFRB translocation partner (i.e. NDE1) in a patient affected by chronic myelomonocytic leukemia (CMMoL) with t(5;16)(q33;p13). Aims. Here we describe the clinical evolution of this patient who responded to IM while developing a clone with trisomy 8 in PDGFRB negative cells. Design and Methods and Results. The patient, affected by Noonan syndrome with PTNP mutation and normal constitutional karyotype, was diagnosed with CMMoL in august 2004, age 30. Sequential hematological and cytogenetic features are shown in Table 1. Following the demonstration of PDGFRB involvement by fluorescence in situ hybridization (FISH), the patient was commenced on IM 400 mg daily on October 2004. After one month, complete hematological response with normal white blood cell count and differential and disappearance of splenomegaly was recorded, along with a major cytogenetic response (Table 1). A complete cytogenetic remission was achieved in October 2005. In December 2007 BM aspirate showed normal morphology, whereas cytogenetic and FISH documented the appearance of a clone with trisomy 8. No evidence of t(5;16) was found by cytogenetics. FISH and molecular (RT-PCR) studies excluded the presence of PDGFRB/NDE1 fusion. Hybridization of chromosome-8-centromeric probe was performed on BM smear and granulocyte precursors showed trisomy 8 in 12/50 cells, whereas only a minority of erythroid precursors (2/30 cells) displayed three signals. Four months later the patient was still on IM, her hematological conditions stable. Trisomy 8 was no more detectable by cytogenetics and FISH. Conclusions. Our finding of a complete response by RT-PCR in a patient with a new variant PDGFRB translocation is noteworthy. The appearance of an unrelated trisomy 8 in IM-sensitive Ph-negative CMPD was not reported before. In our patient +8 was noted 38 months after the start of IM and was no more detectable after 4 months. Fluctuations of the size of the abnormal clone were both described in cases with or without disease transformation (acute myelogenous leukemia, myelodysplastic syndrome). Fluctuating trisomy 8 populations were previously described in MDS. We documented the involvement of the granulocytic lineage by trisomy 8, whereas erythroid cell involvement was of borderline significance. The development of an unrelated clonal abnormality in a patient with IM-sensitive CMPD with PDGFB rearrangement shows that this phenomenon is not restricted to IM-sensitive CML and suggests that it may represent a general phenomenon in CMPD in which the founder clone is inhibited in its growth by an effective drug. Though the development of aneuploidy unrelated with the dominant clone appears to be part of the natural history of , in part reflecting genetic instability, a possible effect TK inhibitors on the mechanisms underlying chromosome segregation at anaphase cannot be ruled out, since TK may be involved in the assembly of the mitotic spindle.