Genetic heterogeneity in transient abnormal myelopoiesis

  • SAIDA Satoshi
    Department of Pediatrics, Graduate School of Medicine, Kyoto University

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Other Title
  • 一過性骨髄異常増殖症における遺伝的多様性
  • イッカセイ コツズイ イジョウ ゾウショクショウ ニ オケル イデンテキ タヨウセイ

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Abstract

Leukemia arises through an evolutionary process of somatic mutation and selection. Transient abnormal myelopoiesis (TAM) is a clonal pre-leukemic disorder that progresses to myeloid leukemia of Down syndrome (ML-DS) through the accumulation of genetic alterations. To investigate the mechanism underlying leukemogenesis, a xenograft model of TAM was established using NOG mice. Serial engraftment after cell transplantation from a TAM patient who developed ML-DS a year later showed the self-renewal capacity of these cells. We detected a GATA1 mutation but no copy number alterations (CNAs) in the primary patient sample by conventional genomic sequencing and CNA profiling. However, engrafted TAM-derived cells showed the emergence of divergent subclones with another GATA1 mutation and various CNAs, including a 16q deletion and 1q gain, both of which are clinically associated with ML-DS. Detailed genetic analysis identified minor subclones with a 16q deletion or this distinct GATA1 mutation in the primary patient sample. These results suggest that genetically heterogeneous subclones with various leukemia-initiating potentials already exist in the neonatal TAM phase, and that ML-DS may develop from a pool of such minor clones through clonal selection. Our xenograft model could be a valuable tool for gaining insight into the processes underlying leukemogenesis.

Journal

  • Rinsho Ketsueki

    Rinsho Ketsueki 56 (12), 2434-2440, 2015

    The Japanese Society of Hematology

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