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  1. Evaluation Summary:

    This paper provides supportive sequencing data for the hypothesis of association between AITL and pre-existing clonal hematopoiesis. It will be of interest to researchers in both lymphoma and myeloid malignancies and raises new hypotheses about the potential smoking-related mechanisms (C>A signature) that may contribute to development of AITL in the background of clonal hematopoiesis. The hypotheses need further validation, as the authors used a small sample and make indirect inferences about the origin of the observed mutations.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

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  2. Reviewer #1 (Public Review):

    This is a carefully performed but largely descriptive analysis of 27 cases of T-cell lymphoma, 25 of whom had AITL. The authors attempted to connect mutations identified in the lymphoma to mutations arising in clonal hematopoiesis (CH) identified in paired bone marrow samples. They also identified differences in mutation patterns between early mutations (primarily C>T, an aging signature) and late mutations (primarily C>A), which they argue is evidence of a smoking signature. They do identify an enrichment of lung cancer among the patients in their cohort compared to rates for other cancers, such as CLL. Finally, they determine that TET2 mutations confer a poorer prognosis among their AITL patients, and show that those with 2 or more TET2 mutations in their CH clones have an increased risk of concurrent hematologic neoplasm (HN).

    Strengths:

    - the analysis of mutation signatures is novel, and the association with smoking, if confirmed, would be an interesting insight.

    Weaknesses:

    - many of the findings reported here have been reported elsewhere, including association between AITL and concurrent myeloid neoplasms earlier this year in Blood Advances (Lewis et al, PMID 32442302), the frequency of mutations in DNMT3A/TET2 in AITL (Couronnee et al, NEJM 2012, Odejide et al, Blood 2014), and the prognostic impact of TET2 mutations in T cell lymphoma (Lemonnier, Blood 2012).

    - To define the likelihood of developing a concurrent hematologic neoplasm among those with multiple TET2 mutations, the authors incorporated the findings from the Lewis paper into their analysis. It appears that they took this straight from the paper, rather than obtaining the primary data (which would have been more robust).

    - the C>A mutation signature can also been an oxidative artifact of sequencing library preparation. It is not clear from the methods or data supplement that the authors considered this possibility.

    - the authors do not appear to have reported smoking history for these patients. If available, pairing smoking data with presence or absence of the C>A mutational signature would be helpful.

    - care must be taken to distinguish these patients, who already have one hematologic neoplasm, from patients with CH who do not have HN. Although two TET2 mutations in this cohort increases the risk of another concurrent HN, one cannot extrapolate the same risk to a non-HN CH population.

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  3. Reviewer #2 (Public Review):

    In this study, Cheng and colleagues use a comparison of mutational landscape in matched AITL tumor samples and Bone marrow sample/peripheral blood to describe the link between clonal hematopoiesis (CH) originating from precursor marrow cells (HSC) and AITL as well as other hematologic malignancies. Using sequential or synchronous samples, they show that myeloid or B-cell neoplasms and AITL can arise from CH. They report enrichment in APOBEC/AID activity-associated substitutions and tobacco smoking associated-substitutions in the variants observed in AITL, the later being associated with a higher risk of lung cancers in their cohort of AITL patients with comparison of epidemiological data. They finally found that the presence of 2 or ore TET2 mutations with >15% VAFs associate with a higher risk of second hematologic malignancy.

    This study is well designed and overall original, based for the first time on a systematic comparison of matched bone marrow/peripheral blood and primary AITL tumors in a series of 25 AITL (angioimmunoblastic T-cell lymphoma) patients, using a large targeted gene panel. Through this original design, the results presented further expand recent reports of the link between clonal hematopoiesis (CH) and AITL, one the most frequent T-cell lymphoma worldwide and also brings important novel findings with potential clinical and biological relevance with respect to the association with APOBEC/AID signature and significance of multiple TET2 mutations with a high allele burden. Overall, the conclusions are fully justified by the obtained data. The main weakness of the study relies on the fact that the association with APOBEC/AID signature, and also with lung cancers is found in the context of a rather limited number of AITL patients (n=25) and, though statistically significant, would ideally require validation in independent publicly available series.

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  4. Reviewer #3 (Public Review):

    This study examined patterns of CH-related mutations in the tumors and matched bone marrow samples from patients with AITL/TFH-PTCL. AITL is an uncommon T-cell lymphoma with a high prevalence of epigenetic mutations (TET2, DNMT3A, IDH2) also typical of age-related CH, and it has association with other hematologic malignancies. The authors suggest that AITL may be derived from a CH stem cell progenitor, which could explain some of the prior associations. This hypothesis has previously emerged because co-occurring mutations were found in B-cells from patients with AITL, and a population-based study discovered a particularly high incidence of T-cell lymphoma among patients with MPNs. The paper confirms the prior observation from a paper by Lewis et al., Blood Adv, 2020, which showed co-occurrence of TET2 and DNMT3A mutations in 22 paired samples of AITL(or TFH-PTCL)/marrow. The present paper additionally provides information about the differential types of single-nucleotide variants among "CH-derived" and "lymphoma specific/late-acquired" mutations, and suggests possible association with tobacco use as a modifying factor (by showing that C>A or "COSMIC Signature 4" mutations are prevalent in AITL-specific mutations but not CH mutations). The authors also report that multiple (>1) TET2 mutations at high VAF (>15%) in CH are associated with subsequent hematologic neoplasms.
    The strength of the paper is reliance on diagnostic samples (as opposed to post-treatment or post-transplantation samples which are known to harbor higher rates of clonal hematopoiesis), and more in-depth evaluation of a few patients who developed other hematologic malignancies before or after AITL.

    The major weakness of the paper is the speculative nature of assignment which mutations may be in which tissue (lymphoma, "HSC", other concurrent myeloid malignancy) based solely VAF %. In only one patient authors substantiate this weak assumption by analysis of purified blood granulocytes. Therefore, the discussion should be prefaced by disclosing this limitation and the "evidence" from data should be really framed as hypotheses which need extensive validation. In particular, it is not clear if CH mutations were in lymphoma (AITL) cells. Some other sources of bias (e.g. immortal-time bias when studying "secondary hematologic cancer-free survival") should also be discussed, and some methodologic aspects need clarification.

    However, these data add to accumulating circumstantial evidence that supports the model of CH as a background for development of AITL and associated hematologic malignancies through sequential acquisition of additional genomic hits that may predispose to T-cell (RHOA), B-cell (EZH2), or myeloid (ASXL1, SRSF3) malignancies.

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