The distribution of MLL breakpoints correlates with outcome in infant acute leukaemia

Abstract

The Brazilian Collaborative Study Group of Infant Acute Leukaemia members are listed in Appendix I as co-authors. SummaryAcute leukaemia in early childhood -and mainly infant leukaemia (IL) -is characterized by acquired genetic alterations, most commonly by the presence of distinct MLL rearrangements (MLL-r). The aim of this study was to investigate possible correlations between clinical features and molecular analyses of a series of 545 childhood leukaemia ( 24 months of age) cases: 385 acute lymphoblastic leukaemia (ALL) and 160 acute myeloid leukaemia (AML). The location of the genomic breakpoints was determined in a subset of 30 MLL-r cases. The overall survival of the investigated cohort was 60Á5%, as determined by the Kaplan-Meier method. Worse outcomes were associated with age at diagnosis 6 months (P < 0Á001), high white blood cell count (P = 0Á001), and MLL-r (P = 0Á002) in ALL, while children with AML displayed a poorer outcome (P = 0Á009) regardless of their age strata. Moreover, we present first evidence that MLL-r patients with poor outcome preferentially displayed chromosomal breakpoints within MLL intron 11. Based on the literature, most MLL-r IL display a breakpoint localization towards intron 11, which in turn may explain their worse clinical course. In summary, the MLL breakpoint localization is of clinical importance and should be considered as a novel outcome predictor for MLL-r patients.

Genomic Inverse PCR for Exploration of Ligated Breakpoints (GIPFEL), a New Method to Detect Translocations in Leukemia

“…Because GIPFEL also gives topical information of the breakpoint location depending on the primer pair yielding a positive readout, a breakpoint distribution chart could be assembled (figure 4). As observed previously, chromosomal junction sites were not randomly distributed but clustered in certain areas corresponding to known hotspots of instability giving additional support to the validity of our GIPFEL results [5], [10]–[20].…”

Relation between Genomic DNA Breakpoints in MLL Gene and Treatment Outcome in Infants with Acute Leukemia

“…Ранее M. Eme renciano и соавт. было продемонстрировано, что локализация точки разрыва в интроне 11 гена MLL ухуд-шает прогноз при ОЛЛ с перестройками 11q23/MLL [21]. В настоящей работе мы по отдельности проанализировали исходы лечения пациентов как с ОЛЛ, так и с ОМЛ.…”

“…Относительно недавно было показано, что общая выживаемость пациентов с MLL-позитивными ОЛ в возрасте младше 24 мес., у которых точка разрыва в ДНК гена MLL локализовалась в интроне 11, была ста-тистически значимо ниже по сравнению с пациентами, у которых точка разрыва находилась в регионе между интронами 7 и 11 [21]. Это связывают с различиями в структуре белка MLL, в частности PHD-доменов (рис.…”

“…Однако в упомянутой выше работе M. Emerenciano и соавт. исследование проводилось в смешанной группе пациентов с ОЛЛ и ОМЛ [21], что не позволяет сделать вывод о роли локализации точек разрыва при ОЛЛ и ОМЛ по отдельности. Кроме того, вызывает сомнения Г.А.…”

Frequency of copy number abnormalities in common genes associated with B-cell precursor acute lymphoblastic leukemia cytogenetic subtypes in Brazilian children

“…ETV6-RUNX1, TCF3-PBX1, and BCR-ABL1 fusion genes were analyzed by reverse transcription PCR as part of the diagnostic procedures. Detection of an MLL-rearrangement (MLL-r) was performed by reverse transcription PCR and by fluorescence in situ hybridization (FISH) (Vysis LSI MLL dual-color break apart rearrangement probe, Abbott Molecular, Abbott Park, IL) as previously described (21).…”