Inherited genetic variation in childhood acute lymphoblastic leukemia

Moriyama, Takaya; Relling, Mary V.; Yang, Jun J.

doi:10.1182/blood-2014-12-580001

Cited by 121 publications

(100 citation statements)

References 108 publications

(82 reference statements)

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“…Recent genome-wide association studies have shown certain single nucleotide polymorphisms in genes like ARID5B, IKZF1, CEBPE, CDKN2A, PIP4K2A, and GATA3 to be associated with an increased risk for developing ALL. 8 However, these findings do not account for the vast majority of cases.…”

Section: Acute Lymphoblastic Leukemiamentioning

confidence: 92%

Progress and Prospects in Pediatric Leukemia

Madhusoodhan

Carroll

Bhatla

2016

Current Problems in Pediatric and Adolescent Health Care

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Section: Acute Lymphoblastic Leukemiamentioning

confidence: 92%

Progress and Prospects in Pediatric Leukemia

Madhusoodhan

Carroll

Bhatla

2016

Current Problems in Pediatric and Adolescent Health Care

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“…The genetic landscape produced by inherited germline variations contributes to leukemogenesis and disease outcome, 31 and is a biological component that contributes to racial, ethnic and other health disparities in ALL. 32 This is particularly relevant in CRLF2 B-ALL which occurs five times more often in Hispanic children than others 28 and comprises more than half of the ALL cases in children with Down Syndrome.…”

mentioning

confidence: 99%

A novel xenograft model to study the role of TSLP-induced CRLF2 signals in normal and malignant human B lymphopoiesis

et al. 2015

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T hymic stromal lymphopoietin (TSLP) stimulates in vitro proliferation of human fetal B-cell precursors. However, its in vivo role during normal human B lymphopoiesis is unknown. Genetic alterations that cause overexpression of its receptor component, cytokine receptor-like factor 2 (CRLF2), lead to high-risk B-cell acute lymphoblastic leukemia implicating this signaling pathway in leukemogenesis. We show that mouse thymic stromal lymphopoietin does not stimulate the downstream pathways (JAK/STAT5 and PI3K/AKT/mTOR) activated by the human cytokine in primary high-risk leukemia with overexpression of the receptor component. Thus, the utility of classic patient-derived xenografts for in vivo studies of this pathway is limited. We engineered xenograft mice to produce human thymic stromal lymphopoietin (+T mice) by injection with stromal cells transduced to express the cytokine. Control (-T) mice were produced using stroma transduced with control vector. Normal levels of human thymic stromal lymphopoietin were achieved in sera of +T mice, but were undetectable in -T mice. Patient-derived xenografts generated from +T as compared to -T mice showed a 3-6-fold increase in normal human B-cell precursors that was maintained through later stages of B-cell development. Gene expression profiles in high-risk B-cell acute lymphoblastic leukemia expanded in +T mice indicate increased mTOR pathway activation and are more similar to the original patient sample than those from -T mice. +T/-T xenografts provide a novel pre-clinical model for understanding this pathway in B lymphopoiesis and identifying treatments for high-risk B-cell acute lymphoblastic leukemia with overexpression of cytokine-like factor receptor 2.

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“…High-risk Ph-like ALL is especially important since it is characterized by tyrosine kinase activation that can be inhibited with currently available pharmacological agents [4,5]. Genomic profiling has also aided identification of inherited risk factors for leukaemia development including GATA3, IKZF1, CEBPE and CKDN2A [6].…”

Section: Dear Readersmentioning

confidence: 99%