Genomic profiling and directed ex vivo drug analysis of an unclassifiable myelodysplastic/myeloproliferative neoplasm progressing into acute myeloid leukemia

Abstract

Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN‐U) are rare genetically heterogeneous hematologic diseases associated with older age and a poor prognosis. If the disease progresses into acute myeloid leukemia (AML), it is often refractory to treatment. To gain insight into genetic alterations associated with disease progression, whole exome sequencing and single nucleotide polymorphism arrays were used to characterize the bone marrow and blood samples from a 39‐year‐old woman at MDS/MPN‐U diagnosis and at AML progression, in which routine genetic diagnostics had not identified any genetic alterations. The data revealed the presence of a partial tandem duplication of the MLL gene as the only detectable copy number change and 11 non‐silent somatic mutations, including DNMT3A R882H and NRAS G13D. All somatic lesions were present both at initial MDS/MPN‐U diagnosis and at AML presentation at similar mutant allele frequencies. The patient has since had two extramedullary relapses and is at high risk of a future bone marrow relapse. A directed ex vivo drug sensitivity analysis showed that the patient's AML cells are sensitive to, for example, the MEK inhibitor trametinib and the proteasome inhibitor bortezomib, indicating that she may benefit from treatment with these drugs. © 2016 Wiley Periodicals, Inc.

Development of a myelodysplastic/myeloproliferative neoplasm-unclassifiable in a patient with acute myeloid leukemia: a case report and literature review

“…Hyrenius-Wittsten et al. 10 reported the genomic profiling and direct ex vivo drug analysis of an MDS/MPN-U that progressed into AML. Takeshita et al.…”

“…In previous studies, aberrant signaling caused by mutations in the RAS/RAF/MEK/ERK pathway and its upstream activators critically contributed to AML or MDS/MPN development. 10,23,24 For this patient, the AML might have alterations in the MEK/ERK pathway. Four years after chemotherapy, because of external environmental exposure or changes in the internal microenvironment, the MEK pathway may have been altered again, leading to the development of MDS/MPN.…”

“…Disease progression in most cases involves general transformation from MPN, MDS, or MDS/MPN into AML, and transformation from AML into MPN, MDS, or MDS/MPN is extremely rare. Hyrenius-Wittsten et al 10 reported the genomic profiling and direct ex vivo drug analysis of an MDS/MPN-U that progressed into AML. Takeshita et al 11 described a case of therapy-related aCML after achieving complete remission from APL, and the aCML rapidly underwent clonal evolution and transformed into CD56-positive AML.…”