ABSTRACT
The functional diversity of cells that compose myeloid malignancies, i.e., the respective roles of genetic and epigenetic heterogeneity in this diversity, remains poorly understood. This question is addressed in chronic myelomonocytic leukemia, a myeloid neoplasm in which clinical diversity contrasts with limited genetic heterogeneity. To generate induced pluripotent stem cell clones, we reprogrammed CD34+ cells collected from a patient with a chronic myelomonocytic leukemia in which whole exome sequencing of peripheral blood monocyte DNA had identified 12 gene mutations, including a mutation in KDM6A and two heterozygous mutations in TET2 in the founding clone and a secondary KRAS(G12D) mutation. CD34+ cells from an age-matched healthy donor were also reprogrammed. We captured a part of the genetic heterogeneity observed in the patient, i.e. we analyzed five clones with two genetic backgrounds, without and with the KRAS(G12D) mutation. Hematopoietic differentiation of these clones recapitulated the main features of the patient's disease, including overproduction of granulomonocytes and dysmegakaryopoiesis. These analyses also disclosed significant discrepancies in the behavior of hematopoietic cells derived from induced pluripotent stem cell clones with similar genetic background, correlating with limited epigenetic changes. These analyses suggest that, beyond the coding mutations, several levels of intraclonal heterogeneity may participate in the yet unexplained clinical heterogeneity of the disease.
Subject(s)
Leukemia, Myelomonocytic, Chronic , Leukemia, Myelomonocytic, Juvenile , Myeloproliferative Disorders , Humans , Leukemia, Myelomonocytic, Chronic/genetics , Leukemia, Myelomonocytic, Juvenile/genetics , Mutation , Exome SequencingABSTRACT
The demonstration that pluripotent stem cells could be generated by somatic cell reprogramming led to wonder if these so-called induced pluripotent stem (iPS) cells would extend our investigation capabilities in the cancer research field. The first iPS cells derived from cancer cells have now revealed the benefits and potential pitfalls of this new model. iPS cells appear to be an innovative approach to decipher the steps of cell transformation as well as to screen the activity and toxicity of anticancer drugs. A better understanding of the impact of reprogramming on cancer cell-specific features as well as improvements in culture conditions to integrate the role of the microenvironment in their behavior may strengthen the epistemic interest of iPS cells as model systems in oncology.
