Tumor suppressor IKZF1 mediates glucocorticoid resistance in B-cell precursor acute lymphoblastic leukemia

Marke, René; Havinga, Jørn; Cloos, Jacqueline; Demkes, Marc; Poelmans, Geert; Yuniati, Laurensia; Schenau, Dorette van Ingen; Sonneveld, Edwin; Waanders, Esmé; Pieters, Rob; Kuiper, Roland P.; Hoogerbrugge, Peter M.; Kaspers, Gertjan J. L.; Leeuwen, Frank N. van; Scheijen, Blanca

doi:10.1038/leu.2015.359

Cited by 47 publications

(51 citation statements)

References 15 publications

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“…Recently, we established that inferior outcome related to IKZF1 deletions in BCP-ALL is correlated with an attenuated in vivo day 8 prednisolone response and increased GC resistance in IKZF1 -deleted primary leukemic cells, as determined by in vitro MTT assays. 6 These results could be recapitulated using primary splenic B cells isolated from Ikzf1 +/− mice, which revealed that non-leukemic Ikzf1 +/− B cells are also less sensitive towards GC-induced apoptosis. 6 Based on our previous findings that BTG1 regulates glucocorticoid receptor activation, 37 we investigated whether loss of BTG1 would impact the GC response in primary murine B cells.…”

Section: Resultsmentioning

confidence: 76%

“…6 These results could be recapitulated using primary splenic B cells isolated from Ikzf1 +/− mice, which revealed that non-leukemic Ikzf1 +/− B cells are also less sensitive towards GC-induced apoptosis. 6 Based on our previous findings that BTG1 regulates glucocorticoid receptor activation, 37 we investigated whether loss of BTG1 would impact the GC response in primary murine B cells. To this end, B cells isolated from WT, Btg1 −/− , Ikzf1 −/− and Btg1 −/− ;Ikzf1 +/− mice, and obtained after lipopolysaccharide activation, were stimulated for 48 hours with increasing concentrations of prednisolone or dexamethasone and subjected to MTS assays to assess relative cell survival.…”

Section: Resultsmentioning

confidence: 76%

“…While Btg1 -deficiency alone had no effect on GC-induced apoptosis, Ikzf1 -haplodeficient B cells showed enhanced cell survival as compared to WT (Figure 4A), similar to our previous findings. 6 Importantly, Btg1 −/− ;Ikzf1 +/− B cells showed an even stronger resistance to GC-induced apoptosis when compared to Ikzf1 +/− B cells ( P <0.001). These findings were confirmed by AnnexinV staining, demonstrating a significantly smaller apoptotic fraction in Btg1 −/− ; Ikzf1 +/− B cells relative to Ikzf1 +/− B cells ( P <0.001) (Figure 4B).…”

Section: Resultsmentioning

confidence: 89%

“…2–5 Recently, we established that loss of IKZF1 affects glucocorticoid (GC)-mediated gene regulation and confers GC resistance in BCP-ALL. 6 Deletion of IKZF1 is a hallmark of BCR-ABL1 -positive BCP-ALL, 7 and within this high-risk cytogenetic subtype, IKZF1 loss is associated with an even worse outcome. 8 IKZF1 gene lesions are also frequently present in high-risk leukemias with a Philadelphia- or BCR-ABL1 -like expression signature, 2,5,9 which often carry activated tyrosine kinases (i.e., ABL1, PDGFRB, JAK2, FLT3 ) or mutations targeting the RAS pathway.…”

Section: Introductionmentioning

confidence: 99%

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Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients

et al. 2016

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Deletions and mutations affecting lymphoid transcription factor IKZF1 (IKAROS) are associated with an increased relapse risk and poor outcome in B-cell precursor acute lymphoblastic leukemia. However, additional genetic events may either enhance or negate the effects of IKZF1 deletions on prognosis. In a large discovery cohort of 533 childhood B-cell precursor acute lymphoblastic leukemia patients, we observed that single-copy losses of BTG1 were significantly enriched in IKZF1-deleted B-cell precursor acute lymphoblastic leukemia (P=0.007). While BTG1 deletions alone had no impact on prognosis, the combined presence of BTG1 and IKZF1 deletions was associated with a significantly lower 5-year event-free survival (P=0.0003) and a higher 5-year cumulative incidence of relapse (P=0.005), when compared with IKZF1-deleted cases without BTG1 aberrations. In contrast, other copy number losses commonly observed in B-cell precursor acute lymphoblastic leukemia, such as CDKN2A/B, PAX5, EBF1 or RB1, did not affect the outcome of IKZF1-deleted acute lymphoblastic leukemia patients. To establish whether the combined loss of IKZF1 and BTG1 function cooperate in leukemogenesis, Btg1-deficient mice were crossed onto an Ikzf1 heterozygous background. We observed that loss of Btg1 increased the tumor incidence of Ikzf1+/− mice in a dose-dependent manner. Moreover, murine B cells deficient for Btg1 and Ikzf1+/− displayed increased resistance to glucocorticoids, but not to other chemotherapeutic drugs. Together, our results identify BTG1 as a tumor suppressor in leukemia that, when deleted, strongly enhances the risk of relapse in IKZF1-deleted B-cell precursor acute lymphoblastic leukemia, and augments the glucocorticoid resistance phenotype mediated by the loss of IKZF1 function.

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Section: Resultsmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients

et al. 2016

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“…Of note, only one of eight IKZF1- altered relapsing cases had initially a poor MRD response and was, therefore, assigned to high-risk treatment, but none of them had initially a poor response to glucocorticoids in vivo , as one might have expected based on in vitro experiments. 45 Yet, IKZF1 -mutated cases had a significantly poorer outcome than their IKZF1 wild-type counterparts as evidenced by an adverse pEFS ( P =0.026) and pOS ( P =0.051; Supplementary Figure 9). …”

Section: Resultsmentioning

confidence: 95%

Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia

Vesely¹,

Frech²,

Eckert

et al. 2016

Leukemia

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Children with P2RY8-CRLF2-positive acute lymphoblastic leukemia have an increased relapse risk. Their mutational and transcriptional landscape, as well as the respective patterns at relapse remain largely elusive. We, therefore, performed an integrated analysis of whole-exome and RNA sequencing in 41 major clone fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras pathway-activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RY8-CRLF2 that was lost in 32% of relapses, all other genomic alterations affecting lymphoid development (58%) and cell cycle (39%) remained stable. Only IKZF1 alterations predominated in relapsing cases (P=0.001) and increased from initially 36 to 58% in matched cases. IKZF1’s critical role is further corroborated by its specific transcriptional signature comprising stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance. Our findings support the notion that P2RY8-CRLF2 is dispensable for relapse development and instead highlight the prominent rank of IKZF1 for relapse development by mediating self-renewal and homing to the bone marrow niche. Consequently, reverting aberrant IKAROS signaling or its disparate programs emerges as an attractive potential treatment option in these leukemias.

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Molecular profiling refines minimal residual disease‐based prognostic assessment in adults with Philadelphia chromosome‐negative B‐cell precursor acute lymphoblastic leukemia

Ribera

Zamora

Vives

et al. 2019

Genes Chromosomes & Cancer

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Minimal residual disease (MRD) assessment is an essential tool in contemporary acute lymphoblastic leukemia (ALL) protocols, being used for therapeutic decisions such as hematopoietic stem cell transplantation in high‐risk patients. However, a significant proportion of adult ALL patients with negative MRD still relapse suggesting that other factors (ie, molecular alterations) must be considered in order to identify those patients with high risk of disease progression. We have identified partial IKZF1 gene deletions and CDKN2A/B deletions as markers of disease recurrence and poor survival in a series of uniformly treated adolescent and adult Philadelphia chromosome‐negative B‐cell progenitor ALL patients treated according to the Programa Español de Tratamientos en Hematología protocols. Importantly, CDKN2A/B deletions showed independent significance of MRD at the end of induction, which points out the need for treatment intensification in these patients despite being MRD‐negative after induction therapy.

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Tumor suppressor IKZF1 mediates glucocorticoid resistance in B-cell precursor acute lymphoblastic leukemia

Cited by 47 publications

References 15 publications

Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients

Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients

Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia

Molecular profiling refines minimal residual disease‐based prognostic assessment in adults with Philadelphia chromosome‐negative B‐cell precursor acute lymphoblastic leukemia

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