Isochromosome 17q in blast crisis of chronic myeloid leukemia and in otherhematologic malignancies is the result of clustered breakpoints in 17p11 and is not associated with coding TP53 mutations

An isochromosome of the long arm of chromosome 17, i(17q), is the most freq uent genetic abnormality observed during the disease progression of Philade lphia chromosome-positive chronic myeloid leukemia (CML), and has been desc ribed as the sole anomaly in various other hematologic malignancies. The i( 17q) hence plays a presumably important pathogenetic role both in leukemia development and progression. This notwithstanding, the molecular consequenc es of this abnormality have not been investigated in detail. We have analyz ed 21 hematologic malignancies (8 CML in blast crisis, 8 myelodysplastic sy ndromes [MDS], 2 acute myeloid leukemias, 2 chronic lymphocytic leukemias, and 1 acute lymphoblastic leukemia) with i(17q) by fluorescence in situ hyb ridization (FISH). Using a yeast artificial chromosome (YAC) contig, derive d from the short arm of chromosome 17, all cases were shown to have a break point in 17p. In 12 cases, the breaks occurred within the Smith-Magenis Syn drome (SMS) common deletion region in 17p11, a gene-rich region which is ge netically unstable. In 10 of these 12 cases, we were able to further map th e breakpoints to specific markers localized within a single YAC clone. Six other cases showed breakpoints located proximally to the SMS common deletio n region, but still within 17p11, and yet another case had a breakpoint dis tal to this region. Furthermore, using chromosome 17 centromere-specific pr obes, it could be shown that the majority of the i(17q) chromosomes (11 of 15 investigated cases) were dicentric, ie, they contained two centromeres, strongly suggesting that i(17q) is formed through an intrachromosomal recom bination event, and also implicating that the i(17q), in a formal sense, sh ould be designated idic(17)(p11). Because i(17q) formation results in loss of 17p material, potentially uncovering the effect of a tumor suppressor on the remaining 17p, the occurrence of TP53 mutations was studied in 17 case s by sequencing the entire coding region. In 16 cases, no TP53 mutations we re found, whereas one MDS displayed a homozygous deletion of TP53. Thus, ou r data suggest that there is no association between i(17q) and coding TP53 mutations, and that another tumor suppressor gene(s), located in proximity of the SMS common deletion region, or in a more distal location, is of path ogenetic importance in i(17q)-associated leukemia. (C) 1999 by The American Society of Hematology.