title: Cryptic and partial deletions of PRDM16 and RUNX1 without t(1;21)(p36;q22) and/or RUNX1-PRDM16 fusion in a case of progressive chronic myeloid leukemia: a complex chromosomal rearrangement of underestimated frequency in disease progression?
abstract: Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence in leukemic stem cells of the Philadelphia chromosome (Ph) and the formation of the BCR-ABL1 fusion. Untreated, the disease progresses to accelerate phase and blast crisis in which hematopoietic differentiation has become arrested. CML progression is frequently associated with cytogenetic evidence of clonal evolution, defined as additional chromosomal aberrations. We here report a CML resistant to tyrosine kinase inhibitors that rapidly progressed to blastic phase. At this time, array CGH performed on CD34(+) cells revealed cryptic partial deletions of both PRDM16 and RUNX1 and duplication of the der(21) chromosome. These genomic rearrangements were confirmed by FISH with probes targeting the deletion on chromosome 21 (24 kb), and with BAC probes flanking the deletion on 1p36 (220 kb). However, no cryptic t(1;21)(p36;q22) and/or RUNX1-PRDM16 were detected, suggesting that these deletions are the residual hallmarks of a more complex mechanism of chromosomal rearrangement, as indicated by the additional inversion of the region bounded by 1p36.32 and 1p36.12 breaks. At the molecular level, these abnormalities lead to the overexpression of the PR-domain negative oncogenic isoform of PRDM16, associated with two deleted copies within the runt domain of C-teminal aberrant RUNX1. These events are not detectable by conventional cytogenetic and molecular strategies, and may be of underestimated frequency in disease progression.
authors.affiliation: Cancer Research Institute of Lille, JP Aubert Center, Inserm Unit 837, Lille, France.
authors.forename: Lauréline
authors.initials: L
authors.lastname: Deluche
authors.forename: Sami
authors.initials: S
authors.lastname: Joha
authors.forename: Sélim
authors.initials: S
authors.lastname: Corm
authors.forename: Agnès
authors.initials: A
authors.lastname: Daudignon
authors.forename: Sandrine
authors.initials: S
authors.lastname: Geffroy
authors.forename: Sabine
authors.initials: S
authors.lastname: Quief
authors.forename: Céline
authors.initials: C
authors.lastname: Villenet
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Kerckaert
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Laï
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.forename: Catherine
authors.initials: C
authors.lastname: Roche-Lestienne