Expression of Ik6 and Ik8 Isoforms and Their Association with Relapse and Death in Mexican Children with Acute Lymphoblastic Leukemia

Reyes-León, Adriana; Juárez-Velázquez, Rocío; Medrano-Hernández, Alma; Cuenca-Roldán, Teresa; Salas-Labadía, Consuelo; Navarrete-Meneses, María del Pilar; Rivera-Luna, Roberto; López-Hernández, Gerardo; Paredes‐Aguilera, Rogelio; Pérez-Vera, Patricia

doi:10.1371/journal.pone.0130756

Cited by 9 publications

(5 citation statements)

References 28 publications

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“…This exclusion criterion could underestimate the frequency of patients with the coexistence of recurrent gene fusions, and CRLF2 rearrangements and overexpression. The incidence of B-ALL among populations, the frequencies of genetic variants for B-ALL susceptibility, and recurrent gene fusion rates are influenced by ethnic differences [33][34][35]. According to our literature review, the coexistence of BCR-ABL1 fusion with CRLF2 rearrangements and overexpression could be more common in Mexican American patients (see supplementary material, Table S1).…”

Section: Concurrence Of Crlf2 Abnormalities With B-all Gene Fusionsmentioning

confidence: 92%

CRLF2 and IKZF1 abnormalities in Mexican children with acute lymphoblastic leukemia and recurrent gene fusions: exploring surrogate markers of signaling pathways

Lorenzana

León

et al. 2021

The Journal of Pathology CR

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The gene fusions BCR‐ABL1, TCF3‐PBX1, and ETV6‐RUNX1 are recurrent in B‐cell acute lymphoblastic leukemia (B‐ALL) and are found with low frequency in coexistence with CRLF2 (cytokine receptor‐like factor 2) rearrangements and overexpression. There is limited information regarding the CRLF2 abnormalities and dominant‐negative IKZF1 isoforms associated with surrogate markers of Jak2, ABL, and Ras signaling pathways. To assess this, we evaluated 24 Mexican children with B‐ALL positive for recurrent gene fusions at diagnosis. We found CRLF2 rearrangements and/or overexpression, dominant‐negative IKZF1 isoforms, and surrogate phosphorylated markers of signaling pathways coexisting with recurrent gene fusions. All the BCR‐ABL1 patients expressed CRLF2 and were positive for pCrkl (ABL); most of them were also positive for pStat5 (Jak2/Stat5) and negative for pErk (Ras). TCF3‐PBX1 patients with CRLF2 abnormalities were positive for pStat5, most of them were also positive for pCrkl, and two patients were also positive for pErk. One patient with ETV6‐RUNX1 and intracellular CRLF2 protein expressed pCrkl. In some cases, the activated signaling pathways were reverted in vitro by specific inhibitors. We further analyzed a TCF3‐PBX1 patient at relapse, identifying a clone with the recurrent gene fusion, P2RY8‐CRLF2, rearrangement, and phosphorylation of the three surrogate markers that we studied. These results agree with the previous reports regarding resistance to treatment observed in patients with recurrent gene fusions and coexisting CRLF2 gene abnormalities. A marker phosphorylation signature was identified in BCR‐ABL1 and TCF3‐PBX1 patients. To obtain useful information for the assessment of treatment in B‐ALL patients with recurrent gene fusions, we suggest that they should be evaluated at diagnosis for CRLF2 gene abnormalities and dominant‐negative IKZF1 isoforms, in addition to the analyses of activation and inhibition of signaling pathways.

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Section: Concurrence Of Crlf2 Abnormalities With B-all Gene Fusionsmentioning

confidence: 92%

CRLF2 and IKZF1 abnormalities in Mexican children with acute lymphoblastic leukemia and recurrent gene fusions: exploring surrogate markers of signaling pathways

Lorenzana

León

et al. 2021

The Journal of Pathology CR

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“…In particular, studies examining the prognostic impact of the IK6-generating intragenic deletion of exons 4-7 have been conflicting. [19][20][21][39][40][41][42][43] 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 Intragenic Deletion Found In Patientsmentioning

confidence: 99%

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

Rogers

Gupta

Reyes³

et al. 2021

Blood Advances

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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 that can be linked to loss of IKAROS protein. IKZF1 knockout and heterozygous null cells displayed relative resistance to a number of common therapies for B-ALL including dexamethasone, 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 IK6 isoform into the endogenous locus and observed a similar drug resistance profile with the exception of retained dexamethasone sensitivity. Interestingly, IKZF1 knockout and IK6 knock-in cells both have significantly increased sensitivity to cytarabine, likely owing to marked downregulation of SAMHD1 after IKZF1 knockout. 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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“…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%

ModelingIKZF1lesions 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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Expression of Ik6 and Ik8 Isoforms and Their Association with Relapse and Death in Mexican Children with Acute Lymphoblastic Leukemia

Cited by 9 publications

References 28 publications

CRLF2 and IKZF1 abnormalities in Mexican children with acute lymphoblastic leukemia and recurrent gene fusions: exploring surrogate markers of signaling pathways

CRLF2 and IKZF1 abnormalities in Mexican children with acute lymphoblastic leukemia and recurrent gene fusions: exploring surrogate markers of signaling pathways

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

ModelingIKZF1lesions in B-ALL reveals distinct chemosensitivity patterns and potential therapeutic vulnerabilities

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