Somatic Mutations and the Risk of Undifferentiated Autoinflammatory Disease in MDS: An Under-Recognized but Prognostically Important Complication

Objectives: We theorized that myelodysplastic syndrome (MDS) with somatic mutations and karyotype abnormalities are associated with autoinflammation, and that the presence of autoinflammatory disease affected prognosis in MDS.Methods: One hundred thirty-four MDS patients were assessed for the prevalence of autoinflammatory complications and its link with karyotypes and somatic mutation status. Autoinflammatory complications were described either as well-defined autoinflammatory diseases (AD) or undifferentiated “autoinflammatory disease” (UAD) (defined as CRP over 10.0 mg/L on five consecutive occasions, taken at separate times and not explained by infection). Several patient characteristics including demographic, clinical, laboratory, cytogenetics charts, and outcomes, were compared between different groups.Results: Sixty-two (46.3%) patients had an autoinflammatory complication manifesting as arthralgia (43.5% vs. 23.6%, p = 0.0146), arthritis (30.6% vs. 15.3%, p = 0.0340), skin rash (27.4% vs. 12.5%, p = 0.0301), pleuritis (14.5% vs. 4.2%, p = 0.0371) and unexplained fever (27.4% vs. 0%, p <0.0001). AD were found in 7.4% of MDS patients (with polymyalgia rheumatic being the most frequently one). Classical autoimmune diseases were found only in 4 MDS patients (3.0%). Transcription factor pathway mutations (RUNX1, BCOR, WTI, TP53) (OR 2.20 [95%CI 1.02–4.75], p = 0.0451) and abnormal karyotypes (OR 2.76 [95%CI 1.22–6.26], p = 0.0153) were associated with autoinflammatory complications. Acute leukaemic transformation was more frequent in MDS patients with autoinflammatory features than those without (27.4% vs. 9.7%, p = 0.0080).Conclusions: Autoinflammatory complications are common in MDS. Somatic mutations of transcription factor pathways and abnormal karyotypes are associated with greater risk of autoinflammatory complications, which are themselves linked to malignant transformation and a worse prognosis

Divergent clonal evolution of blastic plasmacytoid dendritic cell neoplasm and chronic myelomonocytic leukemia from a shared TET2-mutated origin

From Springer Nature via Jisc Publications RouterHistory: received 2020-11-25, rev-recd 2021-02-15, accepted 2021-03-11, registration 2021-03-12, pub-electronic 2021-04-08, online 2021-04-08, pub-print 2021-11Publication status: PublishedFunder: Oglesby Charitable TrustFunder: Pickering family donationFunder: Blood Cancer UK Clinician Scientist Fellowship (15030) Oglesby Charitable Trus

Results of a national UK physician reported survey of COVID-19 infection in patients with a myeloproliferative neoplasm

Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/50110000027

Epigenetic regulator genes direct lineage switching in MLL/AF4 leukaemia

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukaemia resulting in poor clinical outcomes due to resistance towards chemo- and immuno-therapies. Here we show that the myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate from varying differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex, NuRD. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4-positive cell models indicating that lineage switching in MLL/AF4 leukaemia is driven and maintained by disrupted epigenetic regulation

Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer1,2. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease3,4, rapid transformation to acute myeloid leukemia (AML)5, resistance to conventional therapies6–8 and dismal outcomes9. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations10. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R)11. Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response

Multiparameter prediction of myeloid neoplasia risk.

Acknowledgements: This work was funded by an Early Detection Project Grant from Cancer Research UK (EDDCPJT\100010) and a joint grant from the Leukemia and Lymphoma Society (RTF6006-19), and the Rising Tide Foundation for Clinical Cancer Research (CCR-18-500) awarded to G.S.V. The Cambridge Stem Cell Institute is supported by the Wellcome Trust (203151/Z/16/Z, 203151/A/16/Z) and the UKRI Medical Research Council (MC_PC_17230). W.G.D is funded by a Clinical Research Fellowship from the Cancer Research UK Cambridge Centre (CTRQQR-2021\100012). S.P.K. is supported by a UK Research and Innovation (UKRI) Future Leaders Fellowship (MR/T043202/1). P.M.Q. is funded by the Miguel Servet Program (CP20/00130). A.S. is funded by Cancer Research UK (grant 29685) and Blood Cancer UK (grant 503). G.S.V. is supported by a Cancer Research UK Senior Cancer Fellowship (C22324/A23015) and work in his laboratory is also funded by the European Research Council, Kay Kendall Leukemia Fund, Blood Cancer UK and the Wellcome Trust. This research was conducted using the UK Biobank resource under approved application 56844. We thank the participants and investigators involved in the UK Biobank resource and in the other genome-wide association studies cited in this work who collectively made this research possible.The myeloid neoplasms encompass acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms. Most cases arise from the shared ancestor of clonal hematopoiesis (CH). Here we analyze data from 454,340 UK Biobank participants, of whom 1,808 developed a myeloid neoplasm 0-15 years after recruitment. We describe the differences in CH mutational landscapes and hematology/biochemistry test parameters among individuals that later develop myeloid neoplasms (pre-MN) versus controls, finding that disease-specific changes are detectable years before diagnosis. By analyzing differences between 'pre-MN' and controls, we develop and validate Cox regression models quantifying the risk of progression to each myeloid neoplasm subtype. We construct 'MN-predict', a web application that generates time-dependent predictions with the input of basic blood tests and genetic data. Our study demonstrates that many individuals that develop myeloid neoplasms can be identified years in advance and provides a framework for disease-specific prognostication that will be of substantial use to researchers and physicians

Multiparameter prediction of myeloid neoplasia risk.

The myeloid neoplasms encompass acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms. Most cases arise from the shared ancestor of clonal hematopoiesis (CH). Here we analyze data from 454,340 UK Biobank participants, of whom 1,808 developed a myeloid neoplasm 0-15 years after recruitment. We describe the differences in CH mutational landscapes and hematology/biochemistry test parameters among individuals that later develop myeloid neoplasms (pre-MN) versus controls, finding that disease-specific changes are detectable years before diagnosis. By analyzing differences between 'pre-MN' and controls, we develop and validate Cox regression models quantifying the risk of progression to each myeloid neoplasm subtype. We construct 'MN-predict', a web application that generates time-dependent predictions with the input of basic blood tests and genetic data. Our study demonstrates that many individuals that develop myeloid neoplasms can be identified years in advance and provides a framework for disease-specific prognostication that will be of substantial use to researchers and physicians