Abstract

Bone marrow failure (BMF) syndromes, such as severe congenital neutropenia (SCN) are leukemia predisposition syndromes. We focus here on the transition from SCN to pre-leukemic myelodysplastic syndrome (MDS). Stochastic mathematical models have been conceived that attempt to explain the transition of SCN to MDS, in the most parsimonious way, using extensions of standard processes of population genetics and population dynamics, such as the branching and the Moran processes. We previously presented a hypothesis of the SCN to MDS transition, which involves directional selection and recurrent mutation, to explain the distribution of ages at onset of MDS or AML. Based on experimental and clinical data and a model of human hematopoiesis, a range of probable values of the selection coefficient s and mutation rate μ have been determined. These estimates lead to predictions of the age at onset of MDS or AML, which are consistent with the clinical data. In the current paper, based on data extracted from published literature, we seek to provide an independent validation of these estimates. We proceed with two purposes in mind: (i) to determine the ballpark estimates of the selection coefficients and verify their consistency with those previously obtained and (ii) to provide possible insight into the role of recurrent mutations of the G-CSF receptor in the SCN to MDS transition.

Highlights

  • Bone marrow failure (BMF) syndromes, such as severe congenital neutropenia (SCN) are leukemia predisposition syndromes

  • The results of the present paper provide estimates of the selection coefficients that may underlie the fixation of the mutant G-CSF receptor in the SCN to myelodysplastic syndrome (MDS) transition, which are consistent with the range deduced in Wojdyla et al (2019) based on epidemiological evidence

  • Severe congenital neutropenia is not the only inherited BMF syndrome with predisposition to MDS and acute myeloid leukemia (AML); we believe that SCN provides the most robust and accurate disease to model because acquisition of CSF3R mutation is so common (70-80%) as a secondary hit

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Summary

Introduction

Bone marrow failure (BMF) syndromes, such as severe congenital neutropenia (SCN) are leukemia predisposition syndromes. In addition to SCN, these heterogeneous groups of disorders include Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and GATA2 deficiency (West and Churpek, 2017; Kennedy and Shimamura, 2019). Each of these clinically defined disorders are monogenic with mutations in one or more genes in a pathway. What is less well-understood are the somatic mutations that arise during transformation of a BMF syndrome to myeloid neoplasia (Rafei and DiNardo, 2019).

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