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Recurrent NR3C1 Aberrations at First Diagnosis Relate to Steroid Resistance in Pediatric T-Cell Acute Lymphoblastic Leukemia Patients.

ABSTRACT: The glucocorticoid receptor NR3C1 is essential for steroid-induced apoptosis, and deletions of this gene have been recurrently identified at disease relapse for acute lymphoblastic leukemia (ALL) patients. Here, we demonstrate that recurrent NR3C1 inactivating aberrations-including deletions, missense, and nonsense mutations-are identified in 7% of pediatric T-cell ALL patients at diagnosis. These aberrations are frequently present in early thymic progenitor-ALL patients and relate to steroid resistance. Functional modeling of NR3C1 aberrations in pre-B ALL and T-cell ALL cell lines demonstrate that aberrations decreasing NR3C1 expression are important contributors to steroid resistance at disease diagnosis. Relative NR3C1 messenger RNA expression in primary diagnostic patient samples, however, does not correlate with steroid response.

SUBMITTER: van der Zwet JCG

PROVIDER: S-EPMC7755520 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Recurrent <i>NR3C1</i> Aberrations at First Diagnosis Relate to Steroid Resistance in Pediatric T-Cell Acute Lymphoblastic Leukemia Patients.

van der Zwet Jordy C G JCG Smits Willem W Buijs-Gladdines Jessica G C A M JGCAM Pieters Rob R Meijerink Jules P P JPP

HemaSphere 20201221 1

The glucocorticoid receptor NR3C1 is essential for steroid-induced apoptosis, and deletions of this gene have been recurrently identified at disease relapse for acute lymphoblastic leukemia (ALL) patients. Here, we demonstrate that recurrent NR3C1 inactivating aberrations-including deletions, missense, and nonsense mutations-are identified in 7% of pediatric T-cell ALL patients at diagnosis. These aberrations are frequently present in early thymic progenitor-ALL patients and relate to steroid re ...[more]

PMID: 33364552

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Project description:Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, and the second leading cause of pediatric cancer-related death in developed countries. While the cure rate for newly diagnosed ALL is excellent, the genetic heterogeneity and chemoresistance of leukemia cells at relapse makes individualized curative treatment plans difficult. We hypothesize that genetic events would coalesce into a finite number of protein signatures that could guide the design of individualized therapy. Custom reverse-phase protein arrays were produced from pediatric ALL (n = 73) and normal CD34+ (n = 10) samples with 194 validated antibodies. Proteins were allocated into 31 protein functional groups (PFG) to analyze them in the context of other proteins, based on known associations from the literature. The optimal number of protein clusters was determined for each PFG. Protein networks showed distinct transition states, revealing "normal-like" and "leukemia-specific" protein patterns. Block clustering identified strong correlation between various protein clusters that formed 10 protein constellations. Patients that expressed similar recurrent combinations of constellations comprised 7 distinct signatures, correlating with risk stratification, cytogenetics, and laboratory features. Most constellations and signatures were specific for T-cell ALL or pre-B-cell ALL; however, some constellations showed significant overlap. Several signatures were associated with Hispanic ethnicity, suggesting that ethnic pathophysiologic differences likely exist. In addition, some constellations were enriched for "normal-like" protein clusters, whereas others had exclusively "leukemia-specific" patterns.Implications: Recognition of proteins that have universally altered expression, together with proteins that are specific for a given signature, suggests targets for directed combinatorial inhibition or replacement to enable personalized therapy. Mol Cancer Res; 16(8); 1263-74. ©2018 AACRSee related article by Hoff et al., p. 1275.

Dataset Information

Recurrent NR3C1 Aberrations at First Diagnosis Relate to Steroid Resistance in Pediatric T-Cell Acute Lymphoblastic Leukemia Patients.

Publications

Recurrent <i>NR3C1</i> Aberrations at First Diagnosis Relate to Steroid Resistance in Pediatric T-Cell Acute Lymphoblastic Leukemia Patients.

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