How I diagnose and manage individuals at risk for inherited myeloid malignancies

Abstract

Although inherited hematopoietic malignancies have been reported clinically since the early twentieth century, the molecular basis for these diseases has only recently begun to be elucidated. Growing utilization of next-generation sequencing technologies has facilitated the rapid discovery of an increasing number of recognizable heritable hematopoietic malignancy syndromes while also deepening the field's understanding of the molecular mechanisms that underlie these syndromes. Because individuals with inherited hematopoietic malignancies continue to be underdiagnosed and are increasingly likely to be encountered in clinical practice, clinicians need to have a high index of suspicion and be aware of the described syndromes. Here, we present the methods we use to identify, test, and manage individuals and families suspected of having a hereditary myeloid malignancy syndrome. Finally, we address the areas of ongoing research in the field and encourage clinicians and researchers to contribute and collaborate.

Figure 1

Physical manifestations of the known HMMSs. It is vital that the personal and family history include details regarding nonhematopoietic processes as HMMSs can present in a syndromic manner with multiple organ systems involved. Adapted from Churpek and Godley with permission.

Figure 2

The schema used to clinically screen patients for HMMSs based on their personal and family histories. This schema captures the general principles we use in our institution to evaluate all HM patients for HMMSs. *See Table 3. **These samples may not be accepted by some clinical laboratories. CNV, copy number variation; FDR, first-degree relatives; FFPE, formalin-fixed, paraffin-embedded; MSC, mesenchymal stem cell; PBSC, peripheral blood stem cell; SDR, second-degree relatives; WES, whole-exome sequencing; WGS, whole-genome sequencing.

Figure 3

Cellular roles of proteins encoded by genes involved in HMMSs. Pathogenic germline mutations involved in HMMSs affect protein products that are involved in a variety of cellular mechanisms. CEBPA, ETV6, GATA2, RUNX1, and TP53 are transcription factors that localize to the nucleus.^,,,-,,, TERT and TERC both constitute subunits of telomerase and also localize to the nucleus. DDX41 is an RNA helicase and localizes to the cytosol. SRP72 is a ribonucleoprotein that is involved in signal recognition, RNA binding, and cellular trafficking. The function of ankyrin repeat domain-containing protein 26 is not well known, but the protein likely localizes to the inner part of the cell membrane and centrosome. ER, endoplasmic reticulum.