To T or not to B: germline RUNX1 mutation preferences in pediatric ALL predisposition
Serine Avagyan, Anna L. Brown
Serine Avagyan, Anna L. Brown
Published September 1, 2021
Citation Information: J Clin Invest. 2021;131(17):e152464. https://doi.org/10.1172/JCI152464.
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To T or not to B: germline RUNX1 mutation preferences in pediatric ALL predisposition

Abstract

Germline RUNX1 variants have been identified in relation to myeloid malignancy predisposition, with lymphoid hematological malignancies present at a lower frequency in families. In this issue of the JCI, Li and Yang et al. examined the frequency and type of germline RUNX1 variants in pediatric patients with acute lymphoblastic leukemia (ALL). Patients with T cell ALL (T-ALL) harbored rare, damaging RUNX1 mutations that were not seen in patients with B cell ALL (B-ALL). Further, several of the T-ALL–associated RUNX1 variants had potential dominant-negative activity. RUNX1-mutated T-ALL cases were also associated with somatic JAK3 mutations and enriched for the early T cell precursor (ETP) leukemia subtype, a finding that was validated when RUNX1 and JAK3 mutations were combined in mice. This study confirms germline RUNX1 predisposition beyond myeloid malignancy, demonstrates the importance of examining both germline and somatic mutations in malignancy cohorts, and demarcates the ETP ALL subtype as a flag for germline predisposition in patients.

Authors

Serine Avagyan, Anna L. Brown

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Figure 1

Model for B- and T-ALL predisposition.

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Model for B- and T-ALL predisposition. (A) Schematic of B cell developme...
(A) Schematic of B cell development and normal function of known transcription factors involved in B-ALL predisposition. RUNX1 is required for the emergence of developmental hematopoietic stem cells (HSCs), and it also regulates the induction of EBF1 essential for transition to pro-B cell. Germline variants of IKZF1, ETV6, and PAX5 predominantly predispose patients to ALLs, while germline variants in PTPN11, NF1, TP53, and other genes involved in MAPK signaling and DNA damage are associated with both ALL and other malignancies. (B) RUNX1 germline variants reported in Li and Yang et al. (13) (§) and previously published work (*) associate with lymphoid malignancies B-ALL and T-ALL. (C) Damaging germline RUNX1 variants are observed in pediatric T-ALL patients and collaborate with somatic JAK3 mutations, whereas they are absent from pediatric B-ALL patients, with rare examples from other studies in which they are associated with older age of B-ALL onset, but do not have recurrent shared somatic variants. LP, lymphoid progenitor; PreproB,prepro B cell; proB, pro-B cell; preB, pre–B cell; FA, Fanconi anemia; NRDB, negative regulatory domain for DNA binding; TID, transcriptional inhibitory domain.