Clonal hematopoiesis and therapy-related myeloid neoplasms following neuroblastoma treatment

Coorens, Tim; Lü, Wenyu; Mitchell, Emily; Ijaz, Jannat; Roberts, Thomas M.; Oliver, Thomas R. W.; Burke, G A Amos; Gattens, Michael; Dickens, Emmy; Nangalia, Jyoti; Tischkowitz, Marc; Anderson, John; Godfrey, Anna L.; Murray, Matthew J.; Behjati, Sam

doi:10.1182/blood.2020010150

Cited by 26 publications

(22 citation statements)

References 28 publications

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“…Mutational signature analysis. Mutation signatures were fitted to the trinucleotide counts of single-nucleotide variants in the main clone and subclone of ALL (PD38257a) and AML (PD38257c) using the SigFit algorithm 51 and the COSMIC reference database of mutational signatures (https://cancer.sanger.ac.uk/signatures/ sbs/, v3.2), as used previously 52 . Initially, all reference signatures were fitted to the mutation counts.…”

Section: Focus | Articlesmentioning

confidence: 99%

Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia

Khabirova

Jardine

Coorens

et al. 2022

Nat Med

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KMT2A-rearranged infant ALL is an aggressive childhood leukemia with poor prognosis. Here, we investigated the developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia (B-ALL) using bulk messenger RNA (mRNA) meta-analysis and examination of single lymphoblast transcriptomes against a developing bone marrow reference. KMT2A-rearranged infant B-ALL was uniquely dominated by an early lymphocyte precursor (ELP) state, whereas less adverse NUTM1-rearranged infant ALL demonstrated signals of later developing B cells, in line with most other childhood B-ALLs. We compared infant lymphoblasts with ELP cells and revealed that the cancer harbored hybrid myeloid–lymphoid features, including nonphysiological antigen combinations potentially targetable to achieve cancer specificity. We validated surface coexpression of exemplar combinations by flow cytometry. Through analysis of shared mutations in separate leukemias from a child with infant KMT2A-rearranged B-ALL relapsing as AML, we established that KMT2A rearrangement occurred in very early development, before hematopoietic specification, emphasizing that cell of origin cannot be inferred from the transcriptional state.

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Section: Focus | Articlesmentioning

confidence: 99%

Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia

Khabirova

Jardine

Coorens

et al. 2022

Nat Med

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“…t-MN comprises two disease types, namely, therapy-related acute myeloid leukemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS; refs. 15,16). In t-MN genomes, high numbers of clonal platinum-and thiopurine-induced mutations could be observed, which indicated that in these cases clonal expansion of the hematopoietic cell founding the leukemia started after the initiation of exposure (5).…”

Section: Introductionmentioning

confidence: 97%

Elevated Mutational Age in Blood of Children Treated for Cancer Contributes to Therapy-Related Myeloid Neoplasms

et al. 2022

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Childhood cancer survivors are confronted with various chronic health conditions like therapy-related malignancies. However, it is unclear how exposure to chemotherapy contributes to the mutation burden and clonal composition of healthy tissues early in life. Here, we studied mutation accumulation in hematopoietic stem and progenitor cells (HSPC) before and after cancer treatment of 24 children. Of these children, 19 developed therapy-related myeloid neoplasms (t-MN). Posttreatment HSPCs had an average mutation burden increase comparable to what treatment-naïve cells accumulate during 16 years of life, with excesses up to 80 years. In most children, these additional mutations were induced by clock-like processes, which are also active during healthy aging. Other patients harbored mutations that could be directly attributed to treatments like platinum-based drugs and thiopurines. Using phylogenetic inference, we demonstrate that most t-MN in children originate after the start of treatment and that leukemic clones become dominant during or directly after chemotherapy exposure. Significance: Our study shows that chemotherapy increases the mutation burden of normal blood cells in cancer survivors. Only few drugs damage the DNA directly, whereas in most patients, chemotherapy-induced mutations are caused by processes similar to those present during normal aging.

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“…Since BRCA mutations predispose patients to multiple cancer types that generally have an increased sensitivity to platinum-based agents, patients with g BRCA -associated HGOC are more likely to have undergone treatment with platinum and alkylating agents. Platinum chemotherapy specifically appears to cause clonal expansion that can lead to leukemia ( Coorens et al, 2021 ). The platinum effect is suggested by the difference in the observed rates of MDS/AML on PARPi in newly diagnosed vs. relapsed HGOC (<1.5% vs. 8%) and the 4% rate of MDS/AML in the placebo group with relapsed disease ( Poveda et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Baseline risk of hematologic malignancy at initiation of frontline PARP inhibitor maintenance for BRCA1/2-associated ovarian cancer

Navitski

Al-Rawi

Liu

et al. 2021

Gynecologic Oncology Reports

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Highlights PARP inhibitors (PARPi) reduce the risk of ovarian cancer progression and recurrence after response to platinum chemotherapy. Rarely, PARPi are associated with increased risk of hematologic malignancies (MDS/AML) in some patients with ovarian cancer. The causal relationship between PARPi and leukemogenesis is unclear but may be associated with cumulative chemotherapy. We present 3 patients with germline BRCA -associated ovarian cancer and mutations potentially associated with risk of MDS/AML. The clinical benefit of PARPi should be viewed with caution in patients with elevated baseline risk of developing MDS/AML.

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Clonal hematopoiesis and therapy-related myeloid neoplasms following neuroblastoma treatment

Abstract: Syndrome (CAPS) Registry Project Group (European Forum on Antiphospholipid Antibodies). Relapsing catastrophic antiphospholipid syndrome potential role of microangiopathic hemolytic anemia in disease relapses.

Cited by 26 publications

References 28 publications

Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia

Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia

Elevated Mutational Age in Blood of Children Treated for Cancer Contributes to Therapy-Related Myeloid Neoplasms

Baseline risk of hematologic malignancy at initiation of frontline PARP inhibitor maintenance for BRCA1/2-associated ovarian cancer

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