TY - JOUR
T1 - Mechanisms of leukemic transformation in congenital neutropenia
AU - Link, Daniel C.
N1 - Publisher Copyright:
© 2019 Lippincott Williams and Wilkins. All rights reserved.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Purpose of reviewThe 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 findingsAML/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.SummaryBoth 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.
AB - Purpose of reviewThe 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 findingsAML/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.SummaryBoth 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.
KW - Shwachman-Diamond syndrome
KW - TP53
KW - acute myeloid leukemia
KW - granulocyte colony-stimulating factor
KW - granulocyte colony-stimulating factor receptor
KW - myelodysplastic syndrome
KW - severe congenital neutropenia
UR - http://www.scopus.com/inward/record.url?scp=85057528452&partnerID=8YFLogxK
U2 - 10.1097/MOH.0000000000000479
DO - 10.1097/MOH.0000000000000479
M3 - Review article
C2 - 30431463
AN - SCOPUS:85057528452
SN - 1065-6251
VL - 26
SP - 34
EP - 40
JO - Current opinion in hematology
JF - Current opinion in hematology
IS - 1
ER -