Clinical and biological features of PTPN2-deleted adult and pediatric T-cell acute lymphoblastic leukemia

Alcantara, Marion; Simonin, Mathieu; Lhermitte, Ludovic; Touzart, Aurore; Dourthe, Marie Émilie; Latiri, Mehdi; Grardel, Nathalie; Cayuela, Jean Michel; Chalandon, Yves; Graux, Carlos; Dombret, Hervé; Ifrah, Norbert; Petit, Arnaud; Macintyre, Elizabeth; Baruchel, André; Boissel, Nicolas; Asnafi, Vahid

doi:10.1182/bloodadvances.2018028993

Cited by 12 publications

(13 citation statements)

References 35 publications

(60 reference statements)

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“…More generally they provide genetic-based rationale for using drugs targeting the JAK/STAT pathway in IBD, some of which have been recently approved. Of note, deletion of PTPN2 gene has been identified in T-cell acute lymphoblastic leukemia 53,54 . Moreover, our recent work suggests that GOF somatic mutations in JAK1 and STAT3 are main drivers of intestinal malignant lymphoproliferation complicating celiac disease, an autoimmune-like enteropathy driven by dietary gluten.…”

Section: Discussionmentioning

confidence: 99%

Network Analysis of Inflammatory Bowel Disease Reveals PTPN2 As New Monogenic Cause of Intestinal Inflammation

Parlato

Pázmándi

Nian

et al. 2019

Preprint

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54BACKGROUND & AIMS: Genome-wide association studies (GWAS) have uncovered multiple 55 loci associated with inflammatory bowel disease (IBD), yet delineating functional consequences 56 is complex. We used a network-based approach to uncover traits common to monogenic and 57 polygenic forms of IBD in order to reconstruct disease relevant pathways and prioritize causal 58 genes. 59 METHODS:We have used an iterative random walk with restart to explore network 60 neighborhood around the core monogenic IBD cluster and disease-module cohesion to identify 61 functionally relevant GWAS genes. Whole exome sequencing was used to screen a cohort of 62 monogenic IBD for germline mutations in top GWAS genes. One mutation was identified and 63 validated by a combination of biochemical approaches. 64 RESULTS: Monogenic IBD genes clustered siginificantly on the molecular networks and had 65 central roles in network topology. Iterative random walk from these genes allowed to rank the 66 GWAS genes, among which 14 had high disease-module cohesion and were selected as putative 67 causal genes. As a proof of concept, a germline loss of function mutation was identified in PTPN2, 68 one of the top candidates, as a novel genetic etiology of early-onset intestinal autoimmunity. The 69 mutation abolished the catalytic activity of the enzyme, resulting in haploinsufficiency and hyper-70 activation of the JAK/STAT pathway in lymphocytes. 71 CONCLUSIONS: Our network-based approach bridges the gap between large-scale network 72 medicine prediction and single-gene defects and underscores the crucial need of fine tuning the 73 JAK/STAT pathway to preserve intestinal immune homeostasis. Our data provide genetic-based 74 rationale for using drugs targeting the JAK/STAT pathway in IBD.75

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Section: Discussionmentioning

confidence: 99%

Network Analysis of Inflammatory Bowel Disease Reveals PTPN2 As New Monogenic Cause of Intestinal Inflammation

Parlato

Pázmándi

Nian

et al. 2019

Preprint

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“…Both variants consist of an N-terminal catalytic PTP domain followed by a C-terminal domain which includes either a nuclear localization signal or an ER targeting sequence ( Figure 3 ) [ 106 ]. Although PTPN2 deficiency increases JAK-STAT signaling in various cell types, loss-of-function genetic alterations in PTPN2 have been identified mainly in TLX1-expressing T-ALL cases [ 107 , 108 ]. These loss-of-function alterations typically involve mono- or bi-allelic deletions of the entire PTPN2 gene [ 107 ].…”

Section: The Role Of Il-7 Signaling In Acute Lymphoblastic Leukemiamentioning

confidence: 99%

Deregulation of the Interleukin-7 Signaling Pathway in Lymphoid Malignancies

Lodewijckx

Cools

2021

Pharmaceuticals

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The cytokine interleukin-7 (IL-7) and its receptor are critical for lymphoid cell development. The loss of IL-7 signaling causes severe combined immunodeficiency, whereas gain-of-function alterations in the pathway contribute to malignant transformation of lymphocytes. Binding of IL-7 to the IL-7 receptor results in the activation of the JAK-STAT, PI3K-AKT and Ras-MAPK pathways, each contributing to survival, cell cycle progression, proliferation and differentiation. Here, we discuss the role of deregulated IL-7 signaling in lymphoid malignancies of B- and T-cell origin. Especially in T-cell leukemia, more specifically in T-cell acute lymphoblastic leukemia and T-cell prolymphocytic leukemia, a high frequency of mutations in components of the IL-7 signaling pathway are found, including alterations in IL7R, IL2RG, JAK1, JAK3, STAT5B, PTPN2, PTPRC and DNM2 genes.

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“…Aberrant expression of these factors is an element of T-ALL molecular pathogenesis ( Table 1 ). Abnormal expression of specific transcription factors allow division of T-ALL patients into molecular subgroups [ 9 , 29 , 30 , 31 ]. Rearrangements involving the T lymphocyte receptor (T cell antigen receptor, TCR) are common changes in T-ALL and affect from 35% to almost half of patients [ 32 , 33 ].…”

Section: Genetic Profile Of T-allmentioning

confidence: 99%

“…Moreover, PTPN2 deletion is an indicator of better outcome and glucocorticoid response. Lower 5-year OS and higher cumulative incidence of relapse (CIR) were observed in patients without PTPN2 gene deletion compared to patients with a loss of PTPN2 function: 78 vs. 92% and 26 vs. 8%, respectively [ 31 ].…”

Section: Genetic Profile Of T-allmentioning

confidence: 99%

Comprehensive Overview of Gene Rearrangements in Childhood T-Cell Acute Lymphoblastic Leukaemia

Mroczek

Zawitkowska

Kowalczyk

et al. 2021

IJMS

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Acute lymphoblastic leukaemia (ALL) is a relevant form of childhood neoplasm, as it accounts for over 80% of all leukaemia cases. T-cell ALL constitutes a genetically heterogeneous cancer derived from T-lymphoid progenitors. The diagnosis of T-ALL is based on morphologic, immunophenotypic, cytogenetic, and molecular features, thus the results are used for patient stratification. Due to the expression of surface and intracellular antigens, several subtypes of T-ALL can be distinguished. Although the aetiology of T-ALL remains unclear, a wide spectrum of rearrangements and mutations affecting crucial signalling pathways has been described so far. Due to intensive chemotherapy regimens and supportive care, overall cure rates of more than 80% in paediatric T-ALL patients have been accomplished. However, improved knowledge of the mechanisms of relapse, drug resistance, and determination of risk factors are crucial for patients in the high-risk group. Even though some residual disease studies have allowed the optimization of therapy, the identification of novel diagnostic and prognostic markers is required to individualize therapy. The following review summarizes our current knowledge about genetic abnormalities in paediatric patients with T-ALL. As molecular biology techniques provide insights into the biology of cancer, our study focuses on new potential therapeutic targets and predictive factors which may improve the outcome of young patients with T-ALL.

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Clinical and biological features of PTPN2-deleted adult and pediatric T-cell acute lymphoblastic leukemia

Cited by 12 publications

References 35 publications

Network Analysis of Inflammatory Bowel Disease Reveals PTPN2 As New Monogenic Cause of Intestinal Inflammation

Network Analysis of Inflammatory Bowel Disease Reveals PTPN2 As New Monogenic Cause of Intestinal Inflammation

Deregulation of the Interleukin-7 Signaling Pathway in Lymphoid Malignancies

Comprehensive Overview of Gene Rearrangements in Childhood T-Cell Acute Lymphoblastic Leukaemia

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