Congenital neutropenia: disease models guiding new treatment strategies

Abstract

Purpose of review Myeloid diseases are often characterized by a disturbed regulation of myeloid cell proliferation, survival, and maturation. This may either result in a severe paucity of functional neutrophils (neutropenia), an excess production of mature cells (myeloproliferative disorders) or in clonal expansions of dysplastic or immature myeloid cells (myelodysplasia and acute myeloid leukemia). Although these conditions can be regarded as separate entities, caused by the accumulation of distinct sets of somatic gene mutations, it becomes increasingly clear that they may also evolve as the prime consequence of a congenital defect resulting in severe neutropenia. Prominent examples of such conditions include the genetically heterogeneous forms of severe congenital neutropenia (SCN) and Shwachman-Diamond Syndrome. CSF3 treatment is a successful therapy to alleviate neutropenia in the majority of these patients but does not cure the disease nor does it prevent malignant transformation. Allogeneic stem cell transplantation is currently the only therapeutic option to cure SCN, but is relatively cumbersome, e.g., hampered by treatment-related mortality and donor availability. Hence, there is a need for new therapeutic approaches. Recent findings Developments in disease modeling, amongst others based on induced pluripotent stem cell and CRISPR/Cas9 based gene-editing technologies, have created new insights in disease biology and possibilities for treatment. In addition, they are fueling expectations for advanced disease monitoring to prevent malignant transformation. Summary This review highlights the recent progress made in SCN disease modeling and discusses the challenges that are still ahead of us to gain a better understanding of the biological heterogeneity of the disease and its consequences for patient care.

Fast and furious: The neutrophil and its armamentarium in health and disease

“…Defects in neutrophil maturation or differentiation are causative for SCN: a heterogeneous group of rare disorders present at birth. [217][218][219] As emphasized by the name, patients display severe neutropenia-defined as absolute neutrophil counts below 0.5 × 10 9 cells per liter of blood-typically due to a maturation arrest at the promyelocyte stage. The most common causative mutations (accounting for up to 45% of all SCN cases) affect the NE-encoding gene ELANE and culminate in activation of the unfolded protein response and death of myeloid cell progenitors.…”

Precision medicine: The use of tailored therapy in primary immunodeficiencies

“…Several conditions affect phagocytes, both in number and/or function ( 4 ). Congenital neutropenia includes a group of syndromic and non-syndromic conditions with more than two dozen gene defects already described ( 4 , 35 , 36 ). In terms of patient management, prophylactic therapeutics to prevent viral, fungal and bacterial infections are widely used ( 35 ) and it is generally recommended the administration of granulocyte colony stimulating factor (G-CSF) to first increase and then to maintain the neutrophil levels.…”

“…Congenital neutropenia includes a group of syndromic and non-syndromic conditions with more than two dozen gene defects already described ( 4 , 35 , 36 ). In terms of patient management, prophylactic therapeutics to prevent viral, fungal and bacterial infections are widely used ( 35 ) and it is generally recommended the administration of granulocyte colony stimulating factor (G-CSF) to first increase and then to maintain the neutrophil levels. This last treatment contributes to an improvement of life expectancy but is associated to an increased risk of myelodysplastic syndrome and acute myeloid leukaemia ( 35 , 37 ).…”

“…In terms of patient management, prophylactic therapeutics to prevent viral, fungal and bacterial infections are widely used ( 35 ) and it is generally recommended the administration of granulocyte colony stimulating factor (G-CSF) to first increase and then to maintain the neutrophil levels. This last treatment contributes to an improvement of life expectancy but is associated to an increased risk of myelodysplastic syndrome and acute myeloid leukaemia ( 35 , 37 ). Although the use of hematopoietic growth factors can only be considered a semi-tailored treatment in patients with congenital neutropenia, it has been understood in recent years that the response differs between patients and for specific mutations, allowing to tailoring the doses or even the type of myeloid hematopoietic growth factors ( 36 , 37 ).…”

Elastase-dependent congenital neutropenia

“…Here we review the current knowledge and emerging questions regarding how ELANE mutations contribute to a shortage of, and/or dysfunction in neutrophils, and discuss possible strategies that target NE in the context of neutropenia, focusing on ELANE gene editing and NE inhibitors. An overview of the full spectrum of congenital neutropenic disorders is available elsewhere [3][4][5] .…”