Characterization of Genetic Abnormalities at Disease Progression of Chronic Myeloid Leukemia

Research output: ThesisDoctoral Thesis (compilation)


Chronic myeloid leukemia (CML) is a myeloproliferative disorder associated with the translocation t(9;22)(q34;q11) and progresses from a relatively indolent chronic phase (CP) to an accelerated phase (AP) and finally to the more aggressive blast crisis (BC). The general aim of this thesis was to identify and characterize genetic abnormalities occurring at disease progression of CML using molecular cytogenetic, molecular genetic, and bioinformatic analyses. In the first study, multicolor fluorescent in situ hybridization (M-FISH) was used to identify possible cryptic genetic changes in CML BC and AP cases. Two novel and cytogenetically cryptic balanced translocations, t(7;17)(p15;q23) and t(7;17)(q32-34;q23), and an AML-associated translocation, t(9;11)(p21-22;q23), with concomitant rearrangement of the MLL gene, were detected, suggesting that balanced translocations are more common during CML progression than previously indicated by G-banding alone. In the second study, further characterization of the t(7;17)(p15;q23) and t(7;17)(q32-34;q23) showed rearrangement of a novel gene located in 17q23, Musashi-2 (MSI2), encoding a putative RNA-binding protein. In the case with the t(7;17)(p15;q23), a MSI2/HOXA9 fusion transcript was identified, harboring both RNA recognition motif domains of MSI2 and the homeobox domain of HOXA9, suggesting an important role in the disease progression of CML. In the third study, the mechanism of formation of ETV6/ABL1 rearrangement in CML BC, as well as the possible clinical and genetic effects of imatinib treatment, was investigated. FISH analysis revealed that a complex array of chromosomal rearrangements were required for the generation of ETV6/ABL1. Moreover, imatinib treatment resulted in a durable, albeit transient, hematologic and genetic response, lasting approximately three months. Upon disease relapse, no mutations were identified in the SH1 (kinase) domain of ABL1, but a decrease in the expression level of wild-type ETV6 was observed that may have been a contributory factor for the relapse. In the fourth and final study, a detailed mapping of the breakpoints of i(17q) - the most common structural rearrangement observed at disease progression in CML – was performed using locus-specific FISH. In silico analysis of the involved breakpoint region revealed a complex genomic architecture, characterized by large (~ 38-49 kb) palindromic, low-copy repeats (LCR), strongly suggestive of being a genomic feature implicated in the mechanism of formation of i(17q).


  • Aikaterini Barbouti
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics


  • fluorescent in situ hybridization, low-copy repeats, isochromosome 17q, MSI2/HOXA9, ETV6/ABL1, BCR/ABL1, chronic myeloid leukemia, blast crisis, molecular genetics, Clinical genetics, Klinisk genetik
Original languageEnglish
Awarding Institution
Supervisors/Assistant supervisor
  • [unknown], [unknown], Supervisor, External person
Award date2004 Feb 27
  • Anette Welin, Academic Secretary, Department of Clinical Genetics, Lund University Hospital, SE-221 85 Lund, Sweden,
Print ISBNs91-628-5961-7
Publication statusPublished - 2004
Publication categoryResearch

Bibliographic note

Defence details Date: 2004-02-27 Time: 13:00 Place: Lund University Hospital, lecture hall F3 External reviewer(s) Name: Berger, Roland Title: Professor Affiliation: Hôpital Necker, Paris, France --- Article: Barbouti A, Johansson B, Höglund M, Maurtizson N, Strömbeck B, Nilsson PG, Tanke HJ, Hagemeijer A, Mitelman F, and Fioretos T. 2002. Multicolor COBRA-FISH analysis of chronic myeloid leukemia reveals novel cryptic balanced translocations during disease progression. Genes Chromosomes Cancer 35:127-137. Article: Barbouti A, Höglund M, Johansson B, Lassen C, Nilsson PG, Hagemeijer A, Mitelman F, and Fioretos T. 2003. A novel gene, MSI2, encoding a putative RNA-binding protein is recurrently rearranged at disease progression of chronic myeloid leukemia and forms a fusion gene with HOXA9 as a result of the cryptic t(7;17)(p15;q23). Cancer Res 63:1202-1206. Article: Barbouti A, Ahlgren T, Johansson B, Höglund M, Lassen C, Turesson I, Mitelman F, and Fioretos T. 2003. Clinical and genetic studies of ETV6/ABL1-positive chronic myeloid leukaemia in blast crisis treated with imatinib mesylate. Br J Haematol 122:85-93. Article: Barbouti A, Stankiewicz P, Nusbaum C, Cuomo C, Cook A, Höglund M, Johansson B, Hagemeijer A, Park SS, Mitelman F, Lupski JR, and Fioretos T. 2004. The breakpoint region of the most common isochromosome, i(17q), in human neoplasia is characterized by a complex genomic architecture with large palindromic low-copy repeats. Am J Hum Genet 74:1-10.