Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA)

Abstract

Recognition that germline mutations can predispose individuals to blood cancers, often presenting as secondary leukemias, has largely been driven in the last 20 years by studies of families with inherited mutations in the myeloid transcription factors (TFs) RUNX1, GATA2, and CEBPA. As a result, in 2016, classification of myeloid neoplasms with germline predisposition for each of these and other genes was added to the World Health Organization guidelines. The incidence of germline mutation carriers in the general population or in various clinically presenting patient groups remains poorly defined for reasons including that somatic mutations in these genes are common in blood cancers, and our ability to distinguish germline (inherited or de novo) and somatic mutations is often limited by the laboratory analyses. Knowledge of the regulation of these TFs and their mutant alleles, their interaction with other genes and proteins and the environment, and how these alter the clinical presentation of patients and their leukemias is also incomplete. Outstanding questions that remain for patients with these germline mutations or their treating clinicians include: What is the natural course of the disease? What other symptoms may I develop and when? Can you predict them? Can I prevent them? and What is the best treatment? The resolution of many of the remaining clinical and biological questions and effective evidence-based treatment of patients with these inherited mutations will depend on worldwide partnerships among patients, clinicians, diagnosticians, and researchers to aggregate sufficient longitudinal clinical and laboratory data and integrate these data with model systems.

Graphical abstract

Figure 1.

Incidence of different HMs and frequently co-occurring mutations associated with germline TF mutations. Incidence of HMs (first presentation) by age group associated with germline mutations in RUNX1 (n = 123) (A), GATA2 (n = 312) (B), and CEBPA (n = 58) (C). Circos plot showing the relative percentages of frequently co-occurring somatic alterations (mutations and cytogenetic abnormalities) in patients with germline mutations in RUNX1 (D), GATA2 (E), and CEBPA (F). The variables are arranged clockwise in descending order from the most frequent to the least frequent and are distinguished by different colors. The inner circle shows the absolute number of samples with mutations in each gene as indicated. The outer circle shows the percentage of cases with comutation of other genes (indicated by designated gene color from inner circle) for each gene. Co-occurring alterations are also shown as paths emerging from 1 to the other with widths proportional to the number of cases. ALL, acute lymphoblastic leukemia (including T- and B-cell subtypes); AUL, acute undifferentiated leukemia; B-ALL, B-cell acute lymphoblastic leukemia; chr5, del5q; chr7, monosomy 7, del 7q or der (1;7); chr8, trisomy 8; chr21, trisomy 21; Cyto, cytogenetic changes; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; HCL, hairy cell leukemia; JMML, juvenile monocytic leukemia; NHL, non-Hodgkin lymphoma; T-ALL, T-cell acute lymphoblastic leukemia. See supplemental References (available on the Blood Web site).

Figure 2.

Age at onset of first HM in individuals with germline TF mutations. The frequency (%) of the total number of individuals who developed HM (first diagnosis) is plotted for each 10-year age range with germline RUNX1, GATA2), and CEBPA.