A tale of two siblings: two cases of AML arising from a single pre-leukemic DNMT3A mutant clone
Authors: C N Hahn, D M Ross, J Feng, A Beligaswatte, D K Hiwase, W T Parker, M Ho, M Zawitkowski, K L Ambler, G D Cheetham, Y K Lee, M Babic, C M Butcher, G A Engler, A L Brown, R J D'Andrea, I D Lewis, A W Schreiber, L B To, H S Scott
Journal: Leukemia (2015)

Acute myeloid leukemia (AML) patients with DNA methyltransferase 3A (DNMT3A) mutations in remission after induction chemotherapy may have hematopoiesis arising from a putative preleukemic clone lacking the full spectrum of mutations seen at AML diagnosis. 1,2DNMT3A mutations in hematopoietic stem cells lead to increased self-renewal capacity and dominance of the stem-cell compartment. 2The common DNMT3A R882H mutation is usually heterozygous and results in loss-of-function with a dominantnegative effect.DNMT3A mutations are thought to occur early in AML ontogeny, 3 and are found in around 20% of de novo AML and in a higher proportion of secondary AML cases. 4,5In population studies clonal mutations of DNMT3A 6 and other epigenetic regulators are more common with increasing age, and may contribute to a proportion of cases of age-related skewing of X-chromosome inactivation. 1,7Two recent reports from large cohorts identified DNMT3A, Tet methylcytosine dioxygenase 2 (TET2) and additional sex combs like transcriptional regulator 1 (ASXL1; epigenetic modifying genes) as the most commonly mutated genes in peripheral blood samples, 8,9 with a combined prevalence of ⩾ 10% in individuals aged over 65 years.One study provided evidence that individuals with clonal hematopoiesis are more likely to develop hematopoietic malignancy, and examined in detail subsequent myeloid malignancy diagnosis samples together with the initial asymptomatic blood samples for three cases. 8All three cases were found to have multiple (2-6) known pathogenic mutations at the time of asymptomatic blood sampling suggesting that clonal hematopoiesis could be attributed to outgrowth of early leukemic cells.Importantly, a number of the driver mutations were only found upon detailed genetic analysis of the initial blood sample.A similar observation was recently reported in chronic myeloid leukemia, where a DNMT3A mutation that was discovered in molecular remission after treatment was also present in the leukemic clone at diagnosis. 10Hence, although these studies imply that, at least in some cases, a pre-leukemic clone carrying a single epigenetic founder mutation may be present for some time prior to the development of neoplasia, they do not provide direct evidence of its pathogenicity.Here we report direct evidence to fill this knowledge gap that a pre-leukemic clone can evolve to AML.Clonal hematopoiesis (DNMT3A R882H ) was transplanted from an apparently healthy marrow donor to his brother, with subsequent evolution to genetically distinct AML clones in each brother.A healthy 53-yearold man with normal blood counts and bone marrow morphology donated steady-state bone marrow to his 49-year-old brother for treatment of relapsed lymphoma.Fourteen months after the bone marrow transplant, the donor developed normal karyotype AML with mutations in DNMT3A, nucleophosmin 1 (NPM1), and fms-like tyrosine kinase 3 (FLT3).Four months later (18 months postallograft) the recipient developed normal karyotype AML with identical mutations in DNMT3A and NPM1, but wild-type FLT3.Chimerism analysis confirmed donor-derived leukemia.Both brothers received induction chemotherapy and both relapsed after a short-lived remission.