Prognostic impact of IKZF1 deletions in association with vincristine–dexamethasone pulses during maintenance treatment of childhood acute lymphoblastic leukemia on trial ALL-BFM 95

Hinze, Laura; Möricke, Anja; Zimmermann, Martin; Junk, Stefanie V.; Cario, Gunnar; Dağdan, Elif; Kratz, Christian P.; Conter, Valentino; Schrappe, Martin; Stanulla, Martin

doi:10.1038/leu.2017.154

Cited by 20 publications

(16 citation statements)

References 10 publications

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“…The benefit of maintenance vincristine/steroid pulses for patients with IKZF1-deleted ALL was not confirmed by other groups. 89 Furthermore, the COG uses many more maintenance vincristine/steroid pulses than other groups and still finds IKZF1 deletion to be an adverse prognostic factor. Preclinical studies have demonstrated the therapeutic potential of retinoic acid compounds and FAK inhibitors in IKZF1-deleted ALL models, but these approaches have not yet been tested clinically.…”

Section: Abl-class Fusionsmentioning

confidence: 99%

Philadelphia chromosome–like acute lymphoblastic leukemia

Tasian

Loh

Hunger

2017

Blood

209

213

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Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL), also referred to as --like ALL, is a high-risk subset with a gene expression profile that shares significant overlap with that of Ph-positive (Ph) ALL and is suggestive of activated kinase signaling. Although Ph ALL is defined by - fusion, Ph-like ALL cases contain a variety of genomic alterations that activate kinase and cytokine receptor signaling. These alterations can be grouped into major subclasses that include ABL-class fusions involving ABL1, ABL2, CSF1R, and PDGFRB that phenocopy BCR-ABL1 and alterations of CRLF2, JAK2, and EPOR that activate JAK/STAT signaling. Additional genomic alterations in Ph-like ALL activate other kinases, including BLNK, DGKH, FGFR1, IL2RB, LYN, NTRK3, PDGFRA, PTK2B, TYK2, and the RAS signaling pathway. Recent studies have helped to define the genomic landscape of Ph-like ALL and how it varies across the age spectrum, associated clinical features and outcomes, and genetic risk factors. Preclinical studies and anecdotal reports show that targeted inhibitors of relevant signaling pathways are active in specific Ph-like ALL subsets, and precision medicine trials have been initiated for this high-risk ALL subset.

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Section: Abl-class Fusionsmentioning

confidence: 99%

Philadelphia chromosome–like acute lymphoblastic leukemia

Tasian

Loh

Hunger

2017

Blood

209

213

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“…In particular, studies examining the prognostic impact of the IK6-generating intragenic deletion of exons 4-7 have been conflicting. [17][18][19][33][34][35][36][37] Further, in addition to inhibition of residual wild-type IKAROS, the IK6 isoform also heterodimerizes with other IKAROS family proteins such as HELIOS (encoded by IKZF2) and AIOLOS (encoded by IKZF3), inhibiting their function. Therefore, the transcriptomic and phenotypic impact of IK6 could differ from deletion of the entire IKZF1 gene.…”

Section: Gfp-tagged Ik6 Knock-in To the Endogenous Locus Mimics The Imentioning

confidence: 99%

“…16 While IKZF1 mutations and deletions are clinically correlated with poor outcome and increased risk of relapse, indicating IKZF1 status could be a useful prognostic marker, clinical trials to modulate therapeutic intensity based on IKZF1 status have had mixed results. [17][18][19] How the broad spectrum of IKZF1 genetic variants seen in B-ALL affect chemosensitivity and outcome and whether IKZF1 status is a relevant prognostic criterion only in the context of certain driver translocations/mutations remain unclear. 20 Some previously published in vitro studies using RNAi-mediated knockdown of IKZF1 have shown evidence of resistance to corticosteroids, 11,21 but others report no change in chemosensitivity.…”

Section: Introductionmentioning

confidence: 99%

Modeling IKZF1 lesions in B-ALL reveals distinct chemosensitivity patterns and potential therapeutic vulnerabilities

Rogers

Gupta

Reyes

et al. 2020

Preprint

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word count: 249 Figures: 7 Supplemental data: 1 supplemental methods and materials file Number of references: 45 Rogers et al. 2 Key points • Engineered IKZF1 perturbations result in a stem-cell like expression signature, enhanced engraftment in vivo, and multi-drug resistance • Loss of IKAROS may result in new vulnerabilities due to increased sensitivity to cytarabine and upregulation of JAK/STAT and mAb targets Rogers et al. 3 Abstract IKAROS family zinc finger 1 (IKZF1) alterations represent a diverse group of genetic lesions that are associated with an increased risk of relapse in B-lymphoblastic leukemia (B-ALL). Due to the heterogeneity of concomitant lesions it remains unclear how IKZF1 abnormalities directly affect cell function and therapy resistance and whether their consideration as a prognostic indicator is valuable in improving outcome. We used CRISPR/Cas9 to engineer multiple panels of isogeneic lymphoid leukemia cell lines with a spectrum of IKZF1 lesions in order to measure changes in chemosensitivity, gene expression, cell cycle, and in vivo engraftment dynamics that can be directly linked to loss of IKAROS protein. IKZF1 knockout and heterozygous null cells displayed relative resistance to a number of commonly employed therapies for B-ALL including dexamethasone, vincristine, asparaginase, and daunorubicin. Transcription profiling revealed a stem/myeloid cell-like phenotype and JAK/STAT upregulation after IKAROS loss. We also used a CRISPR homology-directed repair (HDR) strategy to knock-in the dominant-negative IK6isoform tagged with GFP into the endogenous locus and observed a similar drug resistance profile with the exception of retained sensitivity to dexamethasone. Interestingly, IKZF1 knockout and IK6 knock-in cells both have significantly increased sensitivity to cytarabine, suggesting intensification of nucleoside analog therapy may be specifically effective for IKZF1-deleted B-ALL. Both types of IKZF1 lesions decreased survival time of xenograft mice, with higher numbers of circulating blasts and increased organ infiltration. Given these findings, exact specification of IKZF1 status in patients may be a beneficial addition to risk stratification and could inform therapy.

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“…Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood but can be cured with modern treatment protocols in more than 80% of cases . However, the mortality rate of ALL still remains high in adults.…”

Section: Introductionmentioning

confidence: 99%

PTPN21‐CDS_long isoform inhibits the response of acute lymphoblastic leukemia cells to NK‐mediated lysis via the KIR/HLA‐I axis

Wang

Zhu

et al. 2020

J of Cellular Biochemistry

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Protein tyrosine phosphatase non-receptor type 21 (PTPN21) is a member of the non-receptor tyrosine phosphatase family. We have found that PTPN21 is mutated in relapsed Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation. PTPN21 consists of three types of isoforms according to the length of the protein encoded. However, the roles of different isoforms in leukemic cells have not been elucidated. In the study, PTPN21 isoform constitution in five ALL cell lines were identified by transcriptome polymerase chain reaction combined with Sanger sequencing, and the relationship between PTPN21 isoforms and sensitivity to natural killer (NK) cells mediated killing in ALL cell lines were further assessed by knock-out of different isoforms of PTPN21 using CRISPR-Cas9 technique. Subsequently, we explored the functional mechanisms through RNA sequencing and confirmatory testing. The results showed that there was no significant change when all PTPN21 isoforms were knocked out in ALL cells, but the sensitivity of NALM6 cells with PTPN21-CDS long knock-out (NALM6-PTPN21 lk ) to NK-mediated killing was significantly increased. Whole transcriptome sequencing and further validation testing showed that human leukocyte antigen class I (HLA-I) molecules were significantly decreased, accompanied by a significantly downregulated expression of antigen presentingrelated chaperones in NALM6-PTPN21 lk cells. Our results uncovered a previously unknown mechanism that PTPN21-CDS long and CDS short isoforms may play opposite roles in NK-mediated killing in ALL cells, and showed that Abbreviations: ALL, acute lymphoblastic leukemia; HLA-I, human leukocyte antigens class I; NK cells, natural killer cells; PCR, polymerase chain reaction; PTPN21, protein tyrosine phosphatase non-receptor type 21.the endogenous PTPN21-CDS long isoform inhibited ALL cells to NK cellmediated lysis by regulating the KIR-HLA-I axis. K E Y W O R D Sacute lymphoblastic leukemia, human leukocyte antigens class I molecules, isoform, NK killing, protein tyrosine phosphatase non-receptor type 21

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Prognostic impact of IKZF1 deletions in association with vincristine–dexamethasone pulses during maintenance treatment of childhood acute lymphoblastic leukemia on trial ALL-BFM 95

Cited by 20 publications

References 10 publications

Philadelphia chromosome–like acute lymphoblastic leukemia

Philadelphia chromosome–like acute lymphoblastic leukemia

Modeling IKZF1 lesions in B-ALL reveals distinct chemosensitivity patterns and potential therapeutic vulnerabilities

PTPN21‐CDS_long isoform inhibits the response of acute lymphoblastic leukemia cells to NK‐mediated lysis via the KIR/HLA‐I axis

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Prognostic impact of IKZF1 deletions in association with vincristine–dexamethasone pulses during maintenance treatment of childhood acute lymphoblastic leukemia on trial ALL-BFM 95

Cited by 20 publications

References 10 publications

Philadelphia chromosome–like acute lymphoblastic leukemia

Philadelphia chromosome–like acute lymphoblastic leukemia

Modeling IKZF1 lesions in B-ALL reveals distinct chemosensitivity patterns and potential therapeutic vulnerabilities

PTPN21‐CDSlong isoform inhibits the response of acute lymphoblastic leukemia cells to NK‐mediated lysis via the KIR/HLA‐I axis

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PTPN21‐CDS_long isoform inhibits the response of acute lymphoblastic leukemia cells to NK‐mediated lysis via the KIR/HLA‐I axis