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Mechanisms of leukemic transformation in congenital neutropenia

Link, Daniel C.

Current Opinion in Hematology: January 2019 - Volume 26 - Issue 1 - p 34–40
doi: 10.1097/MOH.0000000000000479
MYELOID BIOLOGY: Edited by David C. Dale

Purpose of review The development of a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in patients with congenital neutropenia is now the major cause of mortality. Treatment options are limited and there are no effective prevention strategies. This review focuses on mechanisms of leukemic transformation in severe congenital neutropenia (SCN) and Shwachman–Diamond syndrome (SDS), the two most common types of congenital neutropenia.

Recent findings AML/MDS that develops in the setting of congenital neutropenia has distinct molecular features. Clonal hematopoiesis because of TP53 mutations is seen in nearly 50% of patients with SDS, but is not seen in patients with SCN. Accordingly, there is a very high frequency of TP53 mutations in AML/MDS arising in the setting of SDS but not SCN. The rate of mutation accumulation in hematopoietic stem cells (HSCs) from patients with congenital neutropenia is not increased.

Summary Both HSC cell-intrinsic and noncell-intrinsic changes contribute to the development of clonal hematopoiesis in congenital neutropenia and likely accounts for the high rate of leukemic transformation. In SCN, the persistently high levels of granulocyte colony-stimulating factor drive expansion of HSCs carrying truncation mutations of CSF3R. In SDS, impaired ribosome biogenesis induces p53-mediated growth inhibition and drives expansion of HSCs carrying TP53 mutations.

Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA

Correspondence to Daniel C. Link, MD, Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8007, St. Louis, MO 63110, USA. Tel: +1 314 362 8771; fax: +1 314 362 9333; e-mail:

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