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

Blood. 2020 Jul 2;136(1):24-35. doi: 10.1182/blood.2019000937.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Age of Onset
  • Blood Cell Count
  • CCAAT-Enhancer-Binding Proteins / genetics*
  • Core Binding Factor Alpha 2 Subunit / genetics*
  • Disease Management
  • Early Detection of Cancer
  • Forecasting
  • GATA2 Transcription Factor / genetics*
  • Genes, Neoplasm*
  • Genetic Counseling
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • Humans
  • Leukemia, Myeloid, Acute / diagnosis
  • Leukemia, Myeloid, Acute / epidemiology
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / therapy
  • Myelodysplastic Syndromes / genetics
  • Neoplasms, Second Primary / genetics*
  • Penetrance
  • Prognosis

Substances

  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, human
  • Core Binding Factor Alpha 2 Subunit
  • GATA2 Transcription Factor
  • GATA2 protein, human
  • RUNX1 protein, human