Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia

Churchman, Michelle L.; Low, Jonathan; Qu, Chunxu; Paietta, Elisabeth; Kasper, Lawryn H.; Chang, Yunchao; Payne-Turner, Debbie; Althoff, Mark J.; Song, Guangchun; Chen, Shann Ching; Ma, Jing; Rusch, Michael; McGoldrick, Dan; Edmonson, Michael N.; Gupta, Pankaj; Wang, Yong Dong; Caufield, William; Freeman, Burgess B.; Li, Lie; Panetta, John C.; Baker, Sharyn D.; Yang, Yung‐Li; Roberts, Kathryn G.; McCastlain, Kelly; Iacobucci, Ilaria; Peters, Jennifer L.; Centonze, Victoria E.; Notta, Faiyaz; Dobson, Stephanie M.; Zandi, Sasan; Dick, John E.; Janke, Laura J.; Peng, Junmin; Kodali, Kiran; Pagala, Vishwajeeth; Min, Jaeki; Mayasundari, Anand; Williams, Richard; Willman, Cheryl L.; Rowe, Jacob M.; Luger, Selina M.; Dickins, Ross A.; Guy, R. Kiplin; Chen, Taosheng; Mullighan, Charles G.

doi:10.1016/j.ccell.2015.07.016

Cited by 164 publications

(205 citation statements)

References 52 publications

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“…After B-cell lineage specification, IKAROS is again required for the orderly transition through the highly proliferative pre-B-cell stage. Here the importance of IKAROS is underscored by the consequence of reduction in IKAROS activity, which arrests pre-B cells in a premalignant state that can progress to B-ALL that is refractory to anti-leukemic therapy (Joshi et al 2014;Churchman et al 2015). Our current investigation into the molecular mechanisms by which IKAROS controls this critical phase in B-cell precursor differentiation sets a new paradigm for regulation of lineage progression and fidelity that is based on simultaneous positive and negative regulation of superenhancer networks.…”

Section: Discussionmentioning

confidence: 99%

“…Expression of these genes was also examined in leukemic cells generated by transformation of primary IKDN pre-B cells by the oncogenic tyrosine kinase BCR-ABL1 (Roumiantsev et al 2001). These leukemic cells retain the "neuro-epithelial" gene signature and epithelial cell-like phenotypes of primary IKDN pre-B cells (Churchman et al 2015; N Jena, I Joshi, T Yoshida, Z Zhang, Z Liu, P Tata, A Raufi, IM Shapiro, D Weever, JA Pachter, et al, unpubl.). Expression of Tead1/2, Hoxb5, Hoxb6, Hoxb7, and Hoxb8 was increased further in IKDN BCR-ABL1 + leukemic pre-B cells, while the level of native B-cell transcription factors such as Ebf1 was not significantly changed (Fig.…”

Section: Ikaros Represses a Transcriptional Network Of Nonlymphoid Anmentioning

confidence: 99%

“…Notably, upon stromal detachment, IKAROS-deficient but not wild-type large pre-B cells undergo an anoikis type of cell death that is indicative of an epithelial cell-like phenotype supported by distinct mechanisms of survival (Joshi et al 2014). Notably, these epithelial-like properties are retained after IKAROS-deficient large pre-B cells transition to a leukemic stage and may be responsible for the drug resistance and high-risk phenotype attributed to these leukemic cells (Joshi et al 2014;Churchman et al 2015).…”

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confidence: 99%

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Superenhancer reprogramming drives a B-cell–epithelial transition and high-risk leukemia

Zhang

Kashiwagi

et al. 2016

Genes Dev.

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IKAROS is required for the differentiation of highly proliferative pre-B-cell precursors, and loss of IKAROS function indicates poor prognosis in precursor B-cell acute lymphoblastic leukemia (B-ALL). Here we show that IKAROS regulates this developmental stage by positive and negative regulation of superenhancers with distinct lineage affiliations. IKAROS defines superenhancers at pre-B-cell differentiation genes together with B-cell master regulators such as PAX5, EBF1, and IRF4 but is required for a highly permissive chromatin environment, a function that cannot be compensated for by the other transcription factors. IKAROS is also highly enriched at inactive enhancers of genes normally expressed in stem-epithelial cells. Upon IKAROS loss, expression of pre-B-cell differentiation genes is attenuated, while a group of extralineage transcription factors that are directly repressed by IKAROS and depend on EBF1 relocalization at their enhancers for expression is induced. LHX2, LMO2, and TEAD-YAP1, normally kept separate from native B-cell transcription regulators by IKAROS, now cooperate directly with them in a de novo superenhancer network with its own feed-forward transcriptional reinforcement. Induction of de novo superenhancers antagonizes Polycomb repression and superimposes aberrant stem-epithelial cell properties in a B-cell precursor. This dual mechanism of IKAROS regulation promotes differentiation while safeguarding against a hybrid stem-epithelial-B-cell phenotype that underlies high-risk B-ALL.

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Section: Discussionmentioning

confidence: 99%

Section: Ikaros Represses a Transcriptional Network Of Nonlymphoid Anmentioning

confidence: 99%

mentioning

confidence: 99%

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Superenhancer reprogramming drives a B-cell–epithelial transition and high-risk leukemia

Zhang

Kashiwagi

et al. 2016

Genes Dev.

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“…Still, it remains unclear whether and how these factors impact Ikzf1 expression. Studies in leukemic pre-B cells have shown that retinoids up-regulate Ikzf1 expression and imply a role for the retinoic acid receptor family in IKAROS gene regulation and leukemia treatment (Churchman et al 2015).…”

Section: Expression and Immune Cell Phenotypesmentioning

confidence: 99%

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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“…Moreover, preclinical efficacy of retinoids in IKZF1-mutated BCR-ABL1 cell lines and patient-derived xenograft models have been recently described. 36 IKZF1 alterations drive stem cell renewal, cause abnormal bone marrow adhesion, and result in decreased TKI sensitivity. Retinoids have been shown to reverse this phenotype and potentiate TKI activity in IKZF1-altered mouse and human BCR-ABL1 ALL.…”

mentioning

confidence: 99%

Ph-like acute lymphoblastic leukemia

Tran

Loh

2016

Hematology

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Philadelphia chromosome–like acute lymphoblastic leukemia (Ph-like ALL) is a newly identified high-risk (HR) B-lineage ALL subtype, accounting for ∼15% of children with National Cancer Institute–defined HR B-ALL. It occurs more frequently in adolescents and adults, having been reported in as much as 27% of young adults with ALL between 21 and 39 years of age. It exhibits adverse clinical features, confers a poor prognosis, and harbors a diverse range of genetic alterations that activate cytokine receptor genes and kinase signaling pathways, making it amenable to treatment with tyrosine kinase inhibitor (TKI) therapy. Multiple groups are currently conducting clinical trials to prospectively screen patients with Ph-like ALL and incorporate the relevant TKI for those harboring ABL-class gene rearrangements or those with JAK-STAT pathway alterations. The success of combinatorial treatment of TKI with chemotherapy in the setting of Ph-positive ALL suggests that this approach may similarly improve outcomes for patients with Ph-like ALL. Hence, Ph-like ALL illustrates the modern treatment paradigm of precision medicine and presents unique opportunities for harnessing international collaborations to further improve outcomes for patients with ALL.

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Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia

Cited by 164 publications

References 52 publications

Superenhancer reprogramming drives a B-cell–epithelial transition and high-risk leukemia

Superenhancer reprogramming drives a B-cell–epithelial transition and high-risk leukemia

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

Ph-like acute lymphoblastic leukemia

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