MLL partner genes drive distinct gene expression profiles and genomic alterations in pediatric acute myeloid leukemia: an AIEOP study

Abstract

Moreover, for eight patients with mutations in IKZF1 (n ¼ 3), RUNX1 (n ¼ 3), ASXL1 (n ¼ 1), WT1 (n ¼ 2) and IDH1 (n ¼ 2), matched DNA samples from initial diagnosis at chronic phase were available. In none of the chronic phase CML samples were the respective IKZF1 deletions or RUNX1 and ASXL1 mutations detectable, indicating that mutations in IKZF1 and RUNX1 were acquired at the time of transformation to BC-CML, and thus act as driver mutations in these cases. In contrast, WT1 and IDH1 mutations were detected at diagnosis in chronic phase in one case each.With respect to clinical data, associations with survival for RUNX1, ASXL1, IKZF1 and WT1 alterations were investigated. No molecular parameter was significantly associated with outcome, which may be due to the short median survival in BC-CML (n ¼ 34 patients with survival data available; median overall survival: 9.3 months).In conclusion, the aberrant BCR-ABL kinase causes genomic instability of the CML clone by inefficient DNA repair, resulting in chromosomal alterations and molecular aberrations of transcription factors. This study on 12 genes demonstrated for the first time that in 76.9% of the BC-CML patients, molecular mutations are detectable. The high mutation rate of RUNX1 (33.3%), ASXL1 (20.5%) and IKZF1 (17.9%) represented important molecular abnormalities in the progression of CML. In particular, IKZF1 and RUNX1 alterations, both involved in cell differentiation, were identified as important markers of disease progression from chronic phase to BC. Although this is a comprehensive study, further investigations are required to identify additional pathogenetic alterations, as in four cases (10.2%) of our cohort no chromosomal or molecular genetic alterations were observed in addition to t(9;22)(q34;q11). Conflict of interestCH, S Schnittger, WK, and TH have equity ownership of MLL Munich Leukemia Laboratory. VG, AK, MZ, CE, S Schindela, and SW are employed by MLL Munich Leukemia Laboratory. MCM and AH declare no conflict of interest.

MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia

“…MLL-rearranged AML is, in fact, a heterogeneous disease, which depends on the MLL partner gene for its biological and clinical features, such as gene expression and genomic imbalances. 4 Among diverse fusion genes, the 1 that has been consistently associated with the worst outcome both in adult and pediatric AML is MLL-AF6. 9 The t(6;11)(q27;q23) translocation is not rare in childhood AML 3,4 and has been demonstrated to impart a worse prognosis with respect to other forms of MLL-rearranged AML.…”

“…4 Among diverse fusion genes, the 1 that has been consistently associated with the worst outcome both in adult and pediatric AML is MLL-AF6. 9 The t(6;11)(q27;q23) translocation is not rare in childhood AML 3,4 and has been demonstrated to impart a worse prognosis with respect to other forms of MLL-rearranged AML. AF6 is a cytoplasmic protein with 2 distinctive features: 1 single PDZ and 2 rat sarcoma viral oncogene (RAS)-association (RA) domains.…”

“…MLL translocations are detected in up to 80% of infant acute leukemia and in approximately 10% to 15% of childhood acute myeloid leukemia (AML). 3,4 Aberrant proteins resulting from translocations, duplications, or amplifications of the MLL gene cause alteration of the differentiation program with severe effects on leukemogenesis. 5,6 To date, more than 60 fusion partners of MLL have been described, which result in AML, acute lymphoid, and biphenotypic or chemotherapy-related leukemias.…”

“…MLL-rearranged AML is, in fact, a heterogeneous disease, which depends on the MLL partner gene for its biological and clinical features, such as gene expression and genomic imbalances. 4 Among diverse fusion genes, the 1 that has been consistently associated with the worst outcome both in adult and pediatric AML is MLL-AF6. …”

LIN28B is over-expressed in specific subtypes of pediatric leukemia and regulates lncRNA H19

“…(A) Log2 LIN28B expression values in 14 publicly available pediatric leukemia datasets, [3][4][5][6][7][8][9][10][11][12][13][14][15][16] visualized using SinaPlot. Each dot is a patient and red dots represent values above the microarray average.…”