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Lessons Learned from Donor Cell-Derived Myeloid Neoplasms: Report of Three Cases and Review of the Literature.

ABSTRACT: Donor-cell derived myeloid neoplasm (DDMN), a rare complication after allogeneic hematopoietic cell transplantation (HCT), is of interest for its potential to reveal donor-derived and host-derived factors that contribute to the pathogenesis of leukemia. The accurate diagnosis of donor-derived leukemias has been facilitated by the more frequent use of molecular techniques. In this study, we describe three additional cases of DDMN; the first reported case of donor-derived chronic myelomonocytic leukemia (CMML), one acute myeloid leukemia (AML) with t(8;21)(q22;22); RUNX1-RUNX1T1 and one donor-derived MDS with deletion 5q. A review of the cytogenetic profiles of previously reported DDMN indicates a significant contribution of therapy-related myeloid neoplasms. Cases with direct evidence of donor- or recipient-dependent factors are rare; a role of direct transfer of leukemic cells, genomic instability of the donor, abnormal gene methylation in donor cells, proleukemic potential of abnormal stromal niche, and the role of immunological surveillance after transplantation has been observed. The role of additional potential pathogenetic factors that are without clinically observed evidence are also reviewed.

SUBMITTER: Deshmukh KG

PROVIDER: S-EPMC9028156 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Lessons Learned from Donor Cell-Derived Myeloid Neoplasms: Report of Three Cases and Review of the Literature.

Deshmukh Komal Galani KG Kelemen Katalin K

Life (Basel, Switzerland) 20220408 4

Donor-cell derived myeloid neoplasm (DDMN), a rare complication after allogeneic hematopoietic cell transplantation (HCT), is of interest for its potential to reveal donor-derived and host-derived factors that contribute to the pathogenesis of leukemia. The accurate diagnosis of donor-derived leukemias has been facilitated by the more frequent use of molecular techniques. In this study, we describe three additional cases of DDMN; the first reported case of donor-derived chronic myelomonocytic le ...[more]

PMID: 35455050

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Project description:An important pathogenetic distinction in the classification of myeloproliferative neoplasms (MPNs) is the presence or absence of the BCR-ABL fusion gene, which encodes a unique oncogenic tyrosine kinase. The BCR-ABL fusion, caused by the formation of the Philadelphia chromosome (Ph) through translocation, constitutes the disease-initiating event in chronic myeloid leukemia. The development of successive BCR-ABL-targeted tyrosine-kinase inhibitors has led to greatly improved outcomes in patients with chronic myeloid leukemia, including high rates of complete hematologic, cytogenetic, and molecular responses. Such levels of treatment success have long been elusive for patients with Ph-negative MPNs, because of the difficulties in identifying specific driver proteins suitable as drug targets. However, in recent years an improved understanding of the complex pathobiology of classic Ph-negative MPNs, characterized by variable, overlapping multimutation profiles, has prompted the development of better and more broadly targeted (to pathway rather than protein) treatment options, particularly JAK inhibitors. In classic Ph-negative MPNs, overactivation of JAK-dependent signaling pathways is a central pathogenic mechanism, and mutually exclusive mutations in JAK2, MPL, and CALR linked to aberrant JAK activation are now recognized as key drivers of disease progression in myelofibrosis (MF). In clinical trials, the JAK1/JAK2 inhibitor ruxolitinib - the first therapy approved for MF worldwide - improved disease-related splenomegaly and symptoms independent of JAK2 (V617F) mutational status, and prolonged survival compared with placebo or standard therapy in patients with advanced MF. In separate trials, ruxolitinib also provided comprehensive hematologic control in patients with another Ph-negative MPN - polycythemia vera. However, complete cytogenetic or molecular responses with JAK inhibitors alone are normally not observed, underscoring the need for novel combination therapies of JAK inhibitors and complementary agents that better address the complexity of the pathobiology of classic Ph-negative MPNs. Here, we discuss the role of tyrosine-kinase inhibitors in the current MPN-treatment landscape.

Project description:BackgroundGiven the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery.MethodsWe designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent-offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols.ResultsAnalysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3).ConclusionAn efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts.

Dataset Information

Lessons Learned from Donor Cell-Derived Myeloid Neoplasms: Report of Three Cases and Review of the Literature.

Publications

Lessons Learned from Donor Cell-Derived Myeloid Neoplasms: Report of Three Cases and Review of the Literature.

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