INTERNAL TANDEM DUPLICATION OF THE FLT3 GENE IS PREFERENTIALLY SEEN IN ACUTE MYELOID-LEUKEMIA AND MYELODYSPLASTIC SYNDROME AMONG VARIOUS HEMATOLOGICAL MALIGNANCIES - A STUDY ON A LARGE SERIES OF PATIENTS AND CELL-LINES

In this study, we examined a large number of patients to clarify the d istribution and frequency of a recently described FLT3 tandem duplicat ion among hematopoietic malignancies, including 112 acute myelocytic l eukemia (AML), 55 acute lymphoblastic leukemia (ALL), 37 myelodysplast ic syndrome (MDS), 20 chronic myelogenous leukemia (CML), 30 non-Hodgk in's lymphoma (NHL), 14 adult T cell leukemia, 15 chronic lymphocytic leukemia (CLL) and 38 multiple myeloma (MM). We also evaluated 71 cell lines derived from 11 AML, 31 ALL, two hairy cell leukemia, three acu te unclassified leukemia, 10 CML, 12 NHL including six Burkitt's lymph oma, and two MM. Using genomic PCR of exon 11 coding for the juxtamemb rane (JM) domain and first amino acids of the 5'-tyrosine kinase (TK) domain, this length mutation was found only in AML (22/112, 20%) and M DS (1/37). According to the FAB subclassification, they were 5/18 (28% ) of M1, 4/29 (14%) of M2, 3/17 (18%) of M3, 6/24 (25%) of M4, 4/20 (2 0%) of M5 and 1/9 of refractory anemia with excess of blast in transfo rmation. In the various cell lines examined, this abnormality was dete rmined in only one derived from AML and never found in other hematolog ical malignancies. The sequence analysis of the abnormal PCR products revealed that 23 of 24 showed internal tandem duplication with or with out insertion of nucleotides. In one AML, insertion and deletion witho ut duplication was determined. All 24 lengthened sequences were in-fra me. Duplication takes place in the sequence coding for the JM domain a nd leaves the TK domain intact. In conclusion, we emphasize that the l ength mutation of FLT3 at JM/TK-I domains were restricted to AML and M DS. Since all these mutations resulted in in-frame, this abnormality m ight function for the proliferation of leukemic cells.