Dataset Information

Changing of IKZF1 genotype during Philadelphia-negative precursor-B acute lymphoblastic leukemia progression: a short clinical report.

ABSTRACT: •The case demonstrated a rare event of clonal heterogeneity by IKZF1 gene status in BCRABL1- ALL.•IKZF1 deletions are secondary events in ALL caused by clonal evolution during the treatment.•It's prognostic significance could be more crucial in BCR-ABL- rather than in BCR-ABL + ALL.•IKZF1 gene alterations may be determined and proved at the genome, expression and protein level.•IKZF1 deletions are suitable for MRD detection but not stable compared to Ig/TCR rearrangement.

SUBMITTER: Vshyukova V

PROVIDER: S-EPMC4962816 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Changing of IKZF1 genotype during Philadelphia-negative precursor-B acute lymphoblastic leukemia progression: a short clinical report.

Vshyukova Volha V Meleshko Alexander A Mihal Natalia N Aleinikova Olga O

Leukemia research reports 20160627

•The case demonstrated a rare event of clonal heterogeneity by IKZF1 gene status in BCRABL1- ALL.•IKZF1 deletions are secondary events in ALL caused by clonal evolution during the treatment.•It's prognostic significance could be more crucial in BCR-ABL- rather than in BCR-ABL + ALL.•IKZF1 gene alterations may be determined and proved at the genome, expression and protein level.•IKZF1 deletions are suitable for MRD detection but not stable compared to Ig/TCR rearrangement. ...[more]

PMID: 27489764

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Project description:The long-term prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) is still unsatisfactory even after the emergence of tyrosine kinase inhibitors (TKIs) against chimeric BCR-ABL, and this is associated with the high incidence of genetic alterations of Ikaros family zinc finger 1 (IKZF1), most frequently the hemi-allelic loss of exons 4-7 expressing a dominant-negative isoform Ik6. We found that lenalidomide (LEN), a representative of immunomodulatory drugs (IMiDs), which have been long used for the treatment of multiple myeloma, specifically induced accumulation of Ik6 with the disappearance of functional isoforms within 24 h (i.e., abrupt and complete shut-down of the IKZF1 activity) in Ik6-positive Ph+ALL cells in a neddylation-dependent manner. The functional IKZF3 isoforms expression was also abruptly and markedly downregulated. The LEN treatment specifically suppressed proliferation of Ik6-positive-Ph+ALL cells by inducing cell cycle arrest via downregulation of cyclins D3 and E and CDK2, and of importance, markedly upregulated their apoptosis in synergy with the TKI imatinib (IM). Apoptosis of IM-resistant Ph+ALL cells with T315I mutation of BCR-ABL was also upregulated by LEN in the presence of the newly developed TKI ponatinib. Analyses of flow cytometry, western blot, and oligonucleotide array revealed that apoptosis was caspase-/p53-dependent and associated with upregulation of pro-apoptotic Bax/Bim, enhanced dephosphorylation of BCR-ABL/Akt, and downregulation of oncogenic helicase genes HILLS, CDC6, and MCMs4 and 8. Further, the synergism of LEN with IM was clearly documented as a significant prolongation of survival in the xenograft mice model. Because this synergism was further potentiated in vitro by dexamethasone, a key drug for ALL treatment, the strategy of repositioning IMiDs for the treatment of Ik6-positive Ph+ALL patients certainly shed new light on an outpatient-based treatment option for achieving their long-term durable remission and higher QOL, particularly for those who are not tolerable to intensified therapeutic approaches.

Dataset Information

Changing of IKZF1 genotype during Philadelphia-negative precursor-B acute lymphoblastic leukemia progression: a short clinical report.

Publications

Changing of IKZF1 genotype during Philadelphia-negative precursor-B acute lymphoblastic leukemia progression: a short clinical report.

Similar Datasets

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