Transcription factor genetics and biology in predisposition to bone marrow failure and hematological malignancy

Transcription factors (TFs) play a critical role as key mediators of a multitude of developmental pathways, with highly regulated and tightly organized networks crucial for determining both the timing and pattern of tissue development. TFs can act as master regulators of both primitive and definitive hematopoiesis, tightly controlling the behavior of hematopoietic stem and progenitor cells (HSPCs). These networks control the functional regulation of HSPCs including self-renewal, proliferation, and differentiation dynamics, which are essential to normal hematopoiesis. Defining the key players and dynamics of these hematopoietic transcriptional networks is essential to understanding both normal hematopoiesis and how genetic aberrations in TFs and their networks can predispose to hematopoietic disease including bone marrow failure (BMF) and hematological malignancy (HM). Despite their multifaceted and complex involvement in hematological development, advances in genetic screening along with elegant multi-omics and model system studies are shedding light on how hematopoietic TFs interact and network to achieve normal cell fates and their role in disease etiology. This review focuses on TFs which predispose to BMF and HM, identifies potential novel candidate predisposing TF genes, and examines putative biological mechanisms leading to these phenotypes. A better understanding of the genetics and molecular biology of hematopoietic TFs, as well as identifying novel genes and genetic variants predisposing to BMF and HM, will accelerate the development of preventative strategies, improve clinical management and counseling, and help define targeted treatments for these diseases.Jiarna R. Zerella, Claire C. Homan, Peer Arts, Anna L. Brown, Hamish S. Scott, and Christopher N. Hah

GATA2 deficiency syndrome: a decade of discovery

Accepted: 8 August 2021GATA2 deficiency syndrome (G2DS) is a rare autosomal dominant genetic disease predisposing to a range of symptoms of which myeloid malignancy and immunodeficiency including recurrent infections are most common. In the last decade since it was first reported, there have been over 480 individuals identified carrying a pathogenic or likely pathogenic germline GATA2 variant with symptoms of G2DS, with 240 of these confirmed to be familial and 24 de novo. For those that develop myeloid malignancy (75% of all carriers with G2DS disease symptoms), the median age of onset is 17 years (range 0-78 years) and myelodysplastic syndrome (MDS) is the first diagnosis in 75% of these cases with acute myeloid leukemia (AML) in a further 9%. All variant types appear to predispose to myeloid malignancy and immunodeficiency. Apart from lymphedema in which haploinsufficiency seems necessary, the mutational requirements of the other less common G2DS phenotypes is still unclear. These predominantly loss-of-function variants impact GATA2 expression and function in numerous ways including perturbations to DNA binding, protein structure, protein:protein interactions, and gene transcription, splicing and expression. In this review, we provide the first expert-curated ACMG/AMP classification with codes of published variants compatible for use in clinical or diagnostic settings. This article is protected by copyright. All rights reserved.Claire C. Homan, Parvathy Venugopal, Peer Arts, Nur H. Shahrin, Simone Feurstein, Lesley Rawlings, David M. Lawrence, James Andrews, Sarah L. King, Smith, Natasha L. Harvey, Anna L. Brown, Hamish S. Scott, Christopher N. Hah

Allogeneic hematopoietic stem cell transplant outcomes in adults with inherited myeloid malignancies

Final version published online 17 February 2023There is increasing recognition that pathogenic germline variants drive the development of hematopoietic cancers in many individuals. Currently, patients with hereditary hematologic malignancies (HHMs) receive similar standard therapies and hematopoietic stem cell transplant (HSCT) approaches as those with sporadic disease. We hypothesize that patients with myeloid malignancies and deleterious germline predisposition variants have different post-transplant outcomes compared to those without such alleles. We studied 472 patients with myeloid neoplasms, of whom 26% had deleterious germline variants (DGVs) and 34% underwent HSCT. DGVs in CHEK2 and DDX41 were most commonly seen in American and Australian cohorts, respectively. Patients with deleterious germline DDX41 variants had a higher incidence of severe (stage 3-4) acute graft versus host disease (GVHD) (38%) compared to recipients with deleterious CHEK2 variants (0%), other HHM variants (12%), or patients without such germline variants (9%) (p= 0.002). Importantly, the use of post-transplant cyclophosphamide reduced the risk of severe acute GVHD in patients receiving HSCT for deleterious germline DDX41-associated myeloid neoplasms (0% vs 53%, p=0.03). Based on these results, we advocate the use of post-transplant cyclophosphamide when individuals with deleterious germline DDX41 variants undergo allogeneic HSCT for myeloid malignancies, even when transplantation has been performed using wild-type donors.Caner Saygin, Gregory Roloff, Christopher N. Hahn, Rakchha Chhetri, Saar Gill, Hany Elmariah, Chetasi Talati, Emma Nunley, Guimin Gao, Aelin Kim, Michael Bishop, Satyajit Kosuri, Soma Das, Deepak Singhal, Parvathy Venugopal, Claire C. Homan, Anna Brown, Hamish S. Scott, Devendra Hiwase, and Lucy A. Godle

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection ar

Disrupted excitatory synaptic contacts and altered neuronal network activity underpins the neurological phenotype in PCDH19-clustering epilepsy (PCDH19-CE)

Published: 07 January 2021PCDH19-Clustering Epilepsy (PCDH19-CE) is an infantile onset disorder caused by mutation of the X-linked PCDH19 gene. Intriguingly, heterozygous females are affected while hemizygous males are not. While there is compelling evidence that this disorder stems from the coexistence of WT and PCDH19-null cells, the cellular mechanism underpinning the neurological phenotype remains unclear. Here, we investigate the impact of Pcdh19 WT and KO neuron mosaicism on synaptogenesis and network activity. Using our previously established knock-in and knock-out mouse models, together with CRISPR-Cas9 genome editing technology, we demonstrate a reduction in excitatory synaptic contacts between PCDH19-expressing and PCDH19-null neurons. Significantly altered neuronal morphology and neuronal network activities were also identified in the mixed populations. In addition, we show that in Pcdh19 heterozygous mice, where the coexistence of WT and KO neurons naturally occurs, aberrant contralateral axonal branching is present. Overall, our data show that mosaic expression of PCDH19 disrupts physiological neurite communication leading to abnormal neuronal activity, a hallmark of PCDH19-CE.Stefka Mincheva-Tasheva, Alvaro F. Nieto Guil, Claire C. Homan and Jozef Gecz, Paul Q. Thoma

RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML

First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.Anna L. Brown … Andreas W. Schreiber … Claire C. Homan … Richard J. D’Andrea, Ian D. Lewis, Devendra K. Hiwase … Nicola K. Poplawski, Christopher N. Hahn, Hamish S. Scott … et al