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Therapy-related myeloid neoplasms: when genetics and environment collide

Key Points

  • Therapy-related myeloid neoplasms (t-MN) arise as a late effect of chemotherapy and/or radiation administered for a primary condition, often a malignant disease, solid organ transplant or autoimmune disease.

  • The majority of t-MN have high-risk cytogenetic features, and the prognosis for patients with t-MN is poor, with a 5-year survival of 10%.

  • Germline mutations in genes associated with an inherited predisposition to cancer have been identified in approximately 20% of patients with t-MN.

  • Chemotherapy and/or radiotherapy promotes clonal selection of pre-existing, mutant haematopoietic stem cells in addition to directly inducing leukaemogenic mutations.

  • The somatic mutations in t-MN are indistinguishable from those occurring in de novo acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS).

  • Large chromosomal deletions, such as del(5q) and del(7q), that occur in t-MN do not harbour a single, recessive tumour suppressor gene but instead are part of a contiguous gene syndrome (CGS). Moreover, the genes involved in CGSs on these chromosomes act by haploinsufficiency.

  • An aberrant bone marrow microenvironment directly contributes to the pathogenesis of t-MN.

Abstract

Therapy-related myeloid neoplasms (t-MN) arise as a late effect of chemotherapy and/or radiation administered for a primary condition, typically a malignant disease, solid organ transplant or autoimmune disease. Survival is measured in months, not years, making t-MN one of the most aggressive and lethal cancers. In this Review, we discuss recent developments that reframe our understanding of the genetic and environmental aetiology of t-MN. Emerging data are illuminating who is at highest risk of developing t-MN, why t-MN are chemoresistant and how we may use this information to treat and ultimately prevent this lethal disease.

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Figure 1: Risk of therapy-related myeloid neoplasms after chemotherapy in the United States from 1975 to 2008.
Figure 2: Recurrent mutations and cytogenetic abnormalities in therapy-related myeloid neoplasms.
Figure 3: Contiguous gene syndrome regions on chromosomes 5 and 7.
Figure 4: Both intrinsic and extrinsic factors contribute to the development of therapy-related myeloid neoplasms.
Figure 5: Model for the role of clonal selection in the aetiology of high-risk myeloid neoplasms.
Figure 6: A hypothetical approach to preserve healthy haematopoietic stem cells during chemotherapy and/or radiation therapy.

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Acknowledgements

The authors thank Angela Stoddart and Kevin M. Shannon for critical reading of the manuscript. M.E.M. is supported by NIH 1K08CA181254, The V Foundation for Cancer Research (V Foundation Scholar Award), the University of Chicago Medicine Comprehensive Cancer Center CCSG (P30 CA14599), an Institutional Research Grant (IRG-58-004-53-IRG) from the American Cancer Society and the University of Chicago Cancer Research Foundation Auxiliary Board. L.A.G. is supported by grants from the Edward P. Evans Foundation, the Taub Foundation, the Leukemia and Lymphoma Society and the Cancer Research Foundation. M.M.L. is supported by grants from NIH (CA190372) and the Edward P. Evans Foundation.

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M.E.M., L.A.G. and M.M.L. conceived of, wrote and edited the manuscript.

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Correspondence to Michelle M. Le Beau.

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Glossary

Acute myeloid leukaemia

(AML). A cancer of the myeloid lineage of haematopoietic cells associated with an expansion of immature cells (≥20% blasts) and defective differentiation into the mature myeloid lineages.

Myelodysplastic syndrome

(MDS). A group of clonal disorders with dysfunctional and dysplastic haematopoiesis of one or more myeloid lineage(s) leading to decreased maturation of normal myeloid cells with <20% blasts and a risk of leukaemic transformation.

Myelodysplastic/myeloproliferative neoplasms

(MDS/MPN). Clonal haematopoietic malignancy with features of MDS and excess production of one or more myeloid lineages.

Contiguous gene syndrome

(CGS). Genetic disorder caused by chromosomal copy number change, leading to combined dosage imbalance of multiple neighbouring genes typically on the scale of <5 Mb.

Standardized incidence ratio

(SIR). The ratio of the observed-to-expected number of cases based on demographic-specific incidence rates of acute myeloid leukaemia (AML) among the general population.

Fanconi anaemia

A bone marrow failure syndrome associated with an inherited mutation in one of at least 17 specific genes associated with the DNA damage response or DNA repair.

De novo AML

Acute myeloid leukaemia (AML) arising without a prior history of exposure to cytotoxic therapies or pre-existing myeloid neoplasm.

Brachytherapy

The use of radioactive sources implanted into the tumour tissue.

Knudson's two-hit hypothesis

A model stating that tumour suppressor genes are recessive and that inactivation of both alleles is required for a malignant phenotype.

5q– syndrome

A subset of MDS with an interstitial deletion of 5q as the sole cytogenetic abnormality (or with one additional abnormality). These patients present with macrocytic anaemia, megakaryocytic dysplasia and preserved or elevated platelet counts; additionally, they have a relatively favourable prognosis.

Ataxia-pancytopenia syndrome

Also known as myelocerebellar disorder; associated with ataxia, bone marrow failure and a predisposition to myeloid leukaemia with monosomy 7.

Revertant mosaicism

When a disease-causing mutation is spontaneously somatically corrected for and the corrected cell clonally expands.

Shwachman–Diamond syndrome

An inherited disorder associated with skeletal abnormalities, exocrine pancreatic insufficiency and bone marrow failure that may progress to myeloid leukaemia with chromosome 7 abnormalities.

Transition-type mutations

A DNA mutation that changes a purine to a different purine nucleotide or a pyrimidine to a different pyrimidine.

Aplastic anaemia

A disorder characterized by pancytopenia that confers risk of transformation to myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) and occurs as a result of either germline mutations or acquired immune destruction of haematopoietic precursors.

Performance status

Measure of physical functioning of the patient to help predict prognosis.

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McNerney, M., Godley, L. & Le Beau, M. Therapy-related myeloid neoplasms: when genetics and environment collide. Nat Rev Cancer 17, 513–527 (2017). https://doi.org/10.1038/nrc.2017.60

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