Haploinsufficiency of the IKZF1 (IKAROS) tumor suppressor gene cooperates with BCR-ABL in a transgenic model of acute lymphoblastic leukemia

Virely, Clémence; Moulin, Stéphanie; Cobaleda, César; Lasgi, Charlène; Alberdi, A.; Soulier, Jean; Sigaux, François; Chan, Susan; Kastner, Philippe; Ghysdael, Jacques

doi:10.1038/leu.2010.63

Cited by 86 publications

(68 citation statements)

References 14 publications

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“…The constitutively active form of the ABL kinase produced by the Ph + chromosome translocation almost always accompanies IKAROS mutations encountered in high-risk B-ALL (Mullighan et al 2008;Martinelli et al 2009). In line with these genome-wide association studies, in a variety of mouse models, Ikzf1 mutations have been shown to accelerate the development of pre-B-cell leukemias in the context of BCR-ABL1 (Virely et al 2010;Schjerven et al 2013).…”

Section: Ikaros and Polycomb Repression Of A B-cell-epithelial Transimentioning

confidence: 82%

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

Georgopoulos

2017

Genes Dev.

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Lymphocyte differentiation is set to produce myriad immune effector cells with the ability to respond to multitudinous foreign substances. The uniqueness of this developmental system lies in not only the great diversity of cellular functions that it can generate but also the ability of its differentiation intermediates and mature effector cells to expand upon demand, thereby providing lifelong immunity. Surprisingly, the goals of this developmental system are met by a relatively small group of DNA-binding transcription factors that work in concert to control the timing and magnitude of gene expression and fulfill the demands for cellular specialization, expansion, and maintenance. The cellular and molecular mechanisms through which these lineage-promoting transcription factors operate have been a focus of basic research in immunology. The mechanisms of development discerned in this effort are guiding clinical research on disorders with an immune cell base. Here, I focus on IKAROS, one of the earliest regulators of lymphoid lineage identity and a guardian of lymphocyte homeostasis.

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Section: Ikaros and Polycomb Repression Of A B-cell-epithelial Transimentioning

confidence: 82%

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

Georgopoulos

2017

Genes Dev.

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“…The two most frequent secondary aberrations in ETV6-ABL1 ALL (CDKN2A/B and IKZF1 loss) have both been shown to cooperate with BCR-ABL1 during leukemogenesis in mice and likely represent cooperating lesions also in ETV6-ABL1 leukemia. 52,53 These and other CNA recurrently found in our cohort (ATP10, BTLA/CD200) have been associated with an unfavorable prognosis in ALL overall and specifically in BCR-ABL1 and BCR-ABL1-like ALL.…”

Section: Discussionmentioning

confidence: 97%

Characterization of leukemias with ETV6-ABL1 fusion

et al. 2016

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T o characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesions, we analyzed 44 new and published cases of ETV6-ABL1-positive hematologic malignancies [22 cases of acute lymphoblastic leukemia (13 children, 9 adults) and 22 myeloid malignancies (18 myeloproliferative neoplasms, 4 acute myeloid leukemias)]. The presence of the ETV6-ABL1 fusion was ascertained by cytogenetics, fluorescence in-situ hybridization, reverse transcriptase-polymerase chain reaction and RNA sequencing. Genomic and gene expression profiling was performed by single nucleotide polymorphism and expression arrays. Systematic screening of more than 4,500 cases revealed that in acute lymphoblastic leukemia ETV6-ABL1 is rare in childhood (0.17% cases) and slightly more common in adults (0.38%). There is no systematic screening of myeloproliferative neoplasms; however, the number of ETV6-ABL1-positive cases and the relative incidence of acute lymphoblastic leukemia and myeloproliferative neoplasms suggest that in adulthood ETV6-ABL1 is more common in BCR-ABL1-negative chronic myeloid leukemia-like myeloproliferations than in acute lymphoblastic leukemia. The genomic profile of ETV6-ABL1 acute lymphoblastic leukemia resembled that of BCR-ABL1 and BCR-ABL1-like cases with 80% of patients having concurrent CDKN2A/B and IKZF1 deletions. In the gene expression profiling all the ETV6-ABL1-positive samples clustered in close vicinity to BCR-ABL1 cases. All but one of the cases of ETV6-ABL1 acute lymphoblastic leukemia were classified as BCR-ABL1-like by a standardized assay. Over 60% of patients died, irrespectively of the disease or age subgroup examined. In conclusion, ETV6-ABL1 fusion occurs in both lymphoid and myeloid leukemias; the genomic profile and clinical behavior resemble BCR-ABL1-positive malignancies, including the unfavorable prognosis, particularly of acute leukemias. The poor outcome suggests that treatment with tyrosine kinase inhibitors should be considered for patients with this fusion.

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“…(4,17). The knock-in mice expressing the DN Ikaros developed leukemia earlier than the control mice on mating with the BCR-ABL transgenic mice, with fewer additional chromosomal abnormalities (18). These findings suggest that IK6 serves as second hit in BCR-ABL1-mediated leukemogenesis or vice versa.…”

Section: Introductionmentioning

confidence: 56%

IKAROS isoform 6 enhances BCR-ABL1-mediated proliferation of human CD34+ hematopoietic cells on stromal cells

Suzuki

Ono²,

Ohishi³

et al. 2011

Int J Oncol

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Abstract. The BCR-ABL1 induces chronic myelogenous leukemia (CML) and Ph + acute lymphoblastic leukemia (ALL). Recent studies revealed high ratios of loss of the IKZF1 gene which encodes IKAROS in BCR-ABL1 + ALL and lymphoblastic crisis (LBC) of CML. However, little is known about the cooperativity between the aberrant IKAROS and BCR-ABL1 in primary human hematopoietic cells. We investigated the effects of expression of BCR-ABL1 and/or IK6, a natural dominant negative isoform of IKAROS, on proliferation and differentiation of human CD34+ cord blood cells with or without human bone marrow-derived stromal cells which support early B cell differentiation. Cell proliferation was remarkably enhanced by co-expression of BCR-ABL1 and IK6, with reduced expression of glycophorin A and increased expression of CD41, especially on stromal cells, compared with expression of BCR-ABL1 alone that resulted in expansion of erythroid progenitors. Interestingly, p190BCR-ABL1 showed higher dependency on stromal cells to stimulate cell growth with IK6, than p210 BCR-ABL1. Furthermore, the cooperation was found to depend on direct cell adhesive interaction of hematopoietic progenitors with stromal cells. These findings suggest that IK6 and BCR-ABL1 synergistically contribute to leukemogenesis in human bone marrow stromal microenvironment, and may provide a clue to elucidate the mechanisms of leukemogenesis of Ph + ALL and CML-LBC.

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Haploinsufficiency of the IKZF1 (IKAROS) tumor suppressor gene cooperates with BCR-ABL in a transgenic model of acute lymphoblastic leukemia

Cited by 86 publications

References 14 publications

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

Characterization of leukemias with ETV6-ABL1 fusion

IKAROS isoform 6 enhances BCR-ABL1-mediated proliferation of human CD34+ hematopoietic cells on stromal cells

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