Mechanisms of leukemic transformation in congenital neutropenia

Abstract

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 due to 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 non-cell 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 G-CSF 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.

Novel phenotypes observed in patients withETV6-linked leukaemia/familial thrombocytopenia syndrome and a biallelicARID5Brisk allele as leukaemogenic cofactor

“…We recommend that careful genetic counselling be offered before and after genetic testing in cases of familial thrombocytopenia, weighing the indication, medical opportunities and potentially detrimental psychological consequences of its diagnosis similarly to syndromes with germline cancer predisposition 36 37. Further, similar to patients with severe congenital neutropenia or other leukaemia-prone cancer predisposition syndromes, whose long-term risk of developing a haematological malignancy is often linked to the acquisition of additional mutations,7 38 we propose a baseline evaluation and regular clinical follow-up visits according to recently published guidelines 7. The utility to screen for the acquisition of potentially pre-malignant somatic genetic variants in peripheral blood of patients with ETV6 germline mutations (eg , ARID5B , BCOR , RUNX1 , ASXL1 , KMT2A , PAX5 , EPOR , JAK2 , IKZF1 ) has not been demonstrated, but may represent an additional option of monitoring.…”

Síndrome mielodisplásico: aspectos básicos y abordaje diagnóstico

“…En el síndrome Shwachmann-Diamond, por su parte, la incidencia cumulativa a 20 años es de 18.8 % y a 30 años de 36.1 %. (17) El SMD asociado a terapia se incluye en la denominación de neoplasias mieloides relacionadas a terapia y corresponde del 2.3 al 20 % de los casos de SMD. 19 La incidencia en pacientes tratados con quimioterapia puede ser hasta de 6.3 % a 20 años y de 24.3 % a cinco años en aquellos con antecedente de trasplante autólogo de células hematopoyéticas.…”

Intermittent granulocyte maturation arrest, hypocellular bone marrow, and episodic normal neutrophil count can be associated with SRP54 mutations causing Shwachman–Diamond‐like syndrome

“… 3–5 Compared to ELANE mutations, dysgranulopoiesis in SRP54 appears to be more severe. The rate of transformation to acute myeloid leukaemia (AML) /myelodysplasia in SDS has been reported as up to 36·1% at 30 years 8 and early accumulation of TP53 mutations appears to be required 9 . Even though myelodysplasia and AML have not been reported despite long‐lasting follow‐up (up to 46 years), larger cohorts with longer follow‐up are needed to determine the risk of myelodysplasia in SDS‐like patients.…”