New monogenic disorders identify more pathways to neutropenia: from the clinic to next-generation sequencing

Abstract

Neutrophils are the most common type of leukocyte in human circulating blood and constitute one of the chief mediators for innate immunity. Defined as a reduction from a normal distribution of values, neutropenia results from a number of congenital and acquired conditions. Neutropenia may be insignificant, temporary, or associated with a chronic condition with or without a vulnerability to life-threatening infections. As an inherited bone marrow failure syndrome, neutropenia may be associated with transformation to myeloid malignancy. Recognition of an inherited bone marrow failure syndrome may be delayed into adulthood. The list of monogenic neutropenia disorders is growing, heterogeneous, and bewildering. Furthermore, greater knowledge of immune-mediated and drug-related causes makes the diagnosis and management of neutropenia challenging. Recognition of syndromic presentations and especially the introduction of next-generation sequencing are improving the accuracy and expediency of diagnosis as well as their clinical management. Furthermore, identification of monogenic neutropenia disorders is shedding light on the molecular mechanisms of granulopoiesis and myeloid malignancies.

Figure 1.

Presumed sites of differentiation block or cell death in various neutropenias. Mutations in a variety of genes are thought to be responsible for inherited neutropenia: granulocytic lineage factors (black), ribosomal proteins (green), membrane proteins (blue), cytoskeletal proteins (red), or metabolism/intracellular stress factors (brown). HSC, hematopoietic stem cell.

Figure 2.

Proposed pathways for neutropenia. Excessive stress responses, such as the UPR, ER stress, or reactive oxygen species (ROS), may lead to DNA damage, with or without faulty repair by p53-dependent or p53-independent pathways. These events, in turn, may lead to a subsequent block in differentiation or cell death. Other stressful stimuli include radiation exposure, infections, low nutrient supply, or faulty protein synthesis due to defective ribosome assembly. In other cases, neutropenia may result from defective differentiation and release due to receptor/transcription factor defects in signal transduction.