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Loss of Ikaros tumor suppressor function in a mouse model of BCR-ABL1-induced B-ALL correlates with a developmental block at a highly proliferative stage

ABSTRACT: Deletions within the human IKZF1 gene, which encodes Ikaros, a zinc finger transcription factor critical for lymphopoiesis, appear to be the most prominent recurring lesion in human BCR-ABL1+ (Ph+) B-ALL. Furthermore, IKZF1 mutations correlate with poor prognosis of progenitor B-ALL, further strengthening the notion that IKZF1 is a critical tumor suppressor gene in human B-lineage malignancies. To better understand the relationship between Ikzf1 mutations, BCR-ABL, and B-lineage leukemia, we examined the effect of two newly generated Ikzf1 germline mutation on BCR-ABL-induced proliferation and leukemogenesis in vitro and in vivo. We recently showed that deletion of either the exon encoding the first or the fourth DNA-binding zinc finger of Ikaros (IkZnF1-/- and IkZnF4-/-) led to distinct defects in lymphoid development and tumor suppression with de-regulation of distinct subsets of genes, providing a powerful tool for elucidation of Ikaros target genes and mechanism of function. Importantly, IkZnF4-/- had lost Ikaros tumor suppression function, while not abolishing B-cell development. Retroviral expression of BCR-ABL1 p185 in bone marrow cells from the two Ikzf1 mutant strains demonstrated that loss of ZnF4 resulted in expansion of progenitor B cells, with enhanced proliferation in vitro and a less mature cell surface B-cell phenotype in comparison to transduced wild-type bone marrow. Furthermore, in an in vivo model of BCR-ABL+ B-ALL, leukemias generated in the IkZnF4-/- background were more aggressive than those observed in a wild-type background, with cell phenotype corresponding to the in vitro cell cultures. Genome wide high throughput expression analysis (RNA-Seq) revealed a distinct subset of deregulated genes in the IkZnF4-/- BCR-ABL+ in vitro cell cultures, and molecular analysis demonstrated that this in vitro system is amendable for functional studies. These results establish a mouse model for studying the role of Ikzf1 mutations in B-ALL, and for understanding how BCR-ABL collaborates with Ikzf1 mutations to generate aggressive B-ALL.

ORGANISM(S): Mus musculus

PROVIDER: GSE39160 | GEO | 2017/02/06

SECONDARY ACCESSION(S): PRJNA170121

REPOSITORIES: GEO

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Project description:Traditional response criteria in MDS and AML are based on bone marrow morphology and may not accurately reflect tumor burden in patients treated with hypomethylating agents. We used massively parallel sequencing of serial bone marrow samples to monitor MDS and AML tumor burden during treatment with epigenetic therapy (decitabine and panobinostat). Serial bone marrow samples (and skin as a source of normal DNA) from 25 MDS and AML patients were sequenced . We observed that responders, including those in complete remission (CR), can have persistent measurable tumor burden for at least one year without disease progression. Using an ultra-sensitive barcode sequencing approach, we detected extremely rare mutations months to years prior to disease relapse. While patients can live with persistent clonal hematopoiesis in a CR or stable disease, ultimately we find evidence that expansion of a rare subclone can drive relapse or progression. Digital sequencing provides an alternative measure of tumor burden and disease response which may augment traditional clinical response criteria in patients treated with hypomethylating agents and its use should be explored in future clinical trials. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. The Philadelphia chromosome, encoding BCR-ABL1, is the defining lesion of chronic myelogenous leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL) cases. To define oncogenic lesions that cooperate with BCR-ABL1 to induce ALL, we performed genome-wide analysis of leukemic samples from 23 CML cases and 304 ALL cases, including 43 BCR-ABL1 B-ALL cases. IKZF1 (encoding the transcription factor Ikaros) was deleted in 83.7% of BCR-ABL1 B-ALL cases, but not in chronic phase CML. Deletion of IKZF1 was also identified as an acquired lesion in lymphoid blast crisis of CML. The IKZF1 deletions resulted in haploinsufficiency, expression of a dominant negative Ikaros isoform or the complete loss of Ikaros expression. Sequencing of IKZF1 deletion breakpoints suggested that aberrant V(D)J recombination is responsible for the deletions. These findings suggest that genetic lesions resulting in the loss of Ikaros function are a key event in the development of BCR-ABL1 ALL.

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Loss of Ikaros tumor suppressor function in a mouse model of BCR-ABL1-induced B-ALL correlates with a developmental block at a highly proliferative stage

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