Post-transcriptional mechanisms in BCR/ABL leukemogenesis: role of shuttling RNA-binding proteins

Perrotti, Danilo; Calabretta, Bruno

doi:10.1038/sj.onc.1206085

Cited by 48 publications

(39 citation statements)

References 64 publications

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“…For example, both B lineage and T cell ALLs showed an up-regulation of RNA-binding genes and of genes involved in transcription. An altered activity of RNA-binding genes has previously been associated with neoplastic transformation (29). In addition, all three subtypes showed down-regulation of genes involved in cell adhesion, indicating a common defect among all leukemic cases, regardless of lineage.…”

Section: Discussionmentioning

confidence: 84%

Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations

Andersson

Olofsson

Lindgren

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Global expression profiles of a consecutive series of 121 childhood acute leukemias (87 B lineage acute lymphoblastic leukemias, 11 T cell acute lymphoblastic leukemias, and 23 acute myeloid leukemias), six normal bone marrows, and 10 normal hematopoietic subpopulations of different lineages and maturations were ascertained by using 27K cDNA microarrays. Unsupervised analyses revealed segregation according to lineages and primary genetic changes, i.e., TCF3(E2A)͞PBX1, IGH@͞MYC, ETV6(TEL)͞RUNX1(AML1), 11q23͞MLL, and hyperdiploidy (>50 chromosomes). Supervised discriminatory analyses were used to identify differentially expressed genes correlating with lineage and primary genetic change. The gene-expression profiles of normal hematopoietic cells were also studied. By using principal component analyses (PCA), a differentiation axis was exposed, reflecting lineages and maturation stages of normal hematopoietic cells. By applying the three principal components obtained from PCA of the normal cells on the leukemic samples, similarities between malignant and normal cell lineages and maturations were investigated. Apart from showing that leukemias segregate according to lineage and genetic subtype, we provide an extensive study of the genes correlating with primary genetic changes. We also investigated the expression pattern of these genes in normal hematopoietic cells of different lineages and maturations, identifying genes preferentially expressed by the leukemic cells, suggesting an ectopic activation of a large number of genes, likely to reflect regulatory networks of pathogenetic importance that also may provide attractive targets for future directed therapies.

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Section: Discussionmentioning

confidence: 84%

Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations

Andersson

Olofsson

Lindgren

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…27 Some reports discuss likely post-transcriptional mechanisms involving shuttling RNA-binding proteins in leukemogenesis. 28 A number of other genes that encode proteins with RNA-binding domains are rearranged in human cancer. 29 As is the case in TS-2, each of these RNA-binding proteins is fused to a transcription factor with DNA-binding properties, but there is no clear understanding whether, and if so how, their RNA-binding properties contribute to transformation.…”

Section: Resultsmentioning

confidence: 99%

Cooperative transformation by MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins generated by the variant t(1;19) in acute lymphoblastic leukemia

Prima

Hunger

2007

Leukemia

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A variant t(1;19)(q23;p13.3) translocation creates reciprocal DAZAP1/MEF2D and MEF2D/DAZAP1 fusion genes that are expressed in acute lymphoblastic leukemia. We used retroviral gene transfer to ectopically express wild-type and chimeric DAZAP1 and MEF2D fusion proteins in NIH 3T3 cells. In soft agar assays, each of the fusion proteins transformed 3T3 cells with a 20-fold increase in colony formation as compared to empty vector or native MEF2D or DAZAP1 proteins. Co-expression of both DAZAP1/MEF2D and MEF2D/DAZAP1 led to a threefold increase in colony formation as compared to either fusion protein alone. Expression of wild-type DAZAP1, MEF2D or DAZAP1/MEF2D allowed 3T3 cells to proliferate under low serum (0.5%) conditions and suppressed apoptosis. In contrast, MEF2D/DAZAP1 expression did not facilitate proliferation in low serum and led to a modest increase in apoptosis. Both MEF2D/DAZAP1 and DAZAP1/MEF2D have oncogenic properties, and co-expression of both fusion proteins is synergistic.

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“…Studying IKAROS isoform expression in BCR-ABL1 þ pre-B lymphoblastic leukemia, expression of dominantnegative IK6 was detected in six of seven primary cases (cases XIII-XIX in Klein et al, 2004) and two of three cell lines (in BV173 and SUP-B15, but not in Nalm1 cells). As shown by us and others, BCR-ABL1 can induce aberrant splicing of various genes (Perrotti and Calabretta, 2002), including SLP65 (Jumaa et al, 2003;Klein et al, 2004), PYK2 (Salesse et al, 2004) and BTK . Consistent with BCR-ABL1-induced derangement of IKAROS pre-mRNA splicing, patient-derived leukemia cells express dominant-negative IKAROS (IK6) before, but not during extended therapy with the BCR-ABL1 kinase inhibitor STI571 (Figure 2d).…”

Section: Bcr-abl1 Induces Defective Expression Of Ikarosmentioning

confidence: 99%

BCR–ABL1 induces aberrant splicing of IKAROS and lineage infidelity in pre-B lymphoblastic leukemia cells

et al. 2005

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Pre-B lymphoblastic leukemia cells carrying a BCR-ABL1 gene rearrangement exhibit an undifferentiated phenotype. Comparing the genome-wide gene expression profiles of normal B-cell subsets and BCR-ABL1 þ pre-B lymphoblastic leukemia cells by SAGE, the leukemia cells show loss of B lymphoid identity and aberrant expression of myeloid lineage-specific molecules. Consistent with this, BCR-ABL1 þ pre-B lymphoblastic leukemia cells exhibit defective expression of IKAROS, a transcription factor needed for early lymphoid lineage commitment. As shown by inducible expression of BCR-ABL1 in human and murine B-cell precursor cell lines, BCR-ABL1 induces the expression of a dominant-negative IKAROS splice variant, termed IK6. Comparing matched leukemia sample pairs from patients before and during therapy with the BCR-ABL1 kinase inhibitor STI571 (Imatinib), inhibition of BCR-ABL1 partially corrected aberrant expression of IK6 and lineage infidelity of the leukemia cells. To elucidate the contribution of IK6 to lineage infidelity in BCR-ABL1 þ cell lines, IK6 expression was silenced by RNA interference. Upon inhibition of IK6, BCR-ABL1 þ leukemia cells partially restored B lymphoid lineage commitment. Therefore, we propose that BCR-ABL1 induces aberrant splicing of IKAROS, which interferes with lineage identity and differentiation of pre-B lymphoblastic leukemia cells.

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Post-transcriptional mechanisms in BCR/ABL leukemogenesis: role of shuttling RNA-binding proteins

Cited by 48 publications

References 64 publications

Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations

Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations

Cooperative transformation by MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins generated by the variant t(1;19) in acute lymphoblastic leukemia

BCR–ABL1 induces aberrant splicing of IKAROS and lineage infidelity in pre-B lymphoblastic leukemia cells

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