Transcription factor mutations as a cause of familial myeloid neoplasms
Jane E. Churpek, Emery H. Bresnick
Jane E. Churpek, Emery H. Bresnick
Published February 1, 2019
Citation Information: J Clin Invest. 2019;129(2):476-488. https://doi.org/10.1172/JCI120854.
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Review Series

Transcription factor mutations as a cause of familial myeloid neoplasms

Abstract

The initiation and evolution of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are driven by genomic events that disrupt multiple genes controlling hematopoiesis. Human genetic studies have discovered germline mutations in single genes that instigate familial MDS/AML. The best understood of these genes encode transcription factors, such as GATA-2, RUNX1, ETV6, and C/EBPα, which establish and maintain genetic networks governing the genesis and function of blood stem and progenitor cells. Many questions remain unanswered regarding how genes and circuits within these networks function in physiology and disease and whether network integrity is exquisitely sensitive to or efficiently buffered from perturbations. In familial MDS/AML, mutations change the coding sequence of a gene to generate a mutant protein with altered activity or introduce frameshifts or stop codons or disrupt regulatory elements to alter protein expression. Each mutation has the potential to exert quantitatively and qualitatively distinct influences on networks. Consistent with this mechanistic diversity, disease onset is unpredictable and phenotypic variability can be considerable. Efforts to elucidate mechanisms and forge prognostic and therapeutic strategies must therefore contend with a spectrum of patient-specific leukemogenic scenarios. Here we illustrate mechanistic advances in our understanding of familial MDS/AML syndromes caused by germline mutations of hematopoietic transcription factors.

Authors

Jane E. Churpek, Emery H. Bresnick

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Figure 1

Ensuring normal hematopoiesis by establishing and maintaining genetic network integrity.

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Ensuring normal hematopoiesis by establishing and maintaining genetic ne...
The diagram on the left depicts the GATA-2–dependent increase in RUNX1 expression (28, 99), and both independent and collective functions of these transcription factors to establish and maintain genetic networks. The question mark denotes uncertainty as to whether RUNX1 might control GATA-2 expression. The diagram on the right depicts how an inhibitory GATA-2 C-finger mutation corrupts network integrity. The model assumes that network integrity ensures normal hematopoiesis, and numerous opportunities exist to corrupt integrity, thereby creating a predisposition or vulnerability to a battery of genetic or environmental insults that trigger pathogenesis. For simplicity, the diagram illustrates GATA-2 and RUNX1 actions, yet numerous components are involved, including other genes and their respective proteins subject to germline mutations that create a predisposition for MDS/AML, e.g., C/EBPα. In addition, there may be instances in which GATA-2–dependent pathogenesis is independent of RUNX1 and vice versa. The rectangles at the bottom represent individual genes, with the colors representing variable levels of gene activity. The white rectangles within the corrupted network reflect little or no transcriptional regulation. Red X, blocked path; hatched line, disrupted regulatory connection. N, N-finger; C, C-finger; RHD, Runt homology domain; TAD, transactivation domain.