Compartment-specific mutational landscape of clonal hematopoiesis

Hartmann, Luise; Hecker, Judith; Rothenberg‐Thurley, Maja; Rivière, Jennifer; Jentzsch, Madlen; Ksienzyk, Bianka; Buck, Michèle C.; Garde, Mark van der; Fischer, Luise; Winter, Susann; Rauner, Martina; Tsourdi, Elena; Weidner, Heike; Sockel, Katja; Schneider, Moritz; Kubasch, Anne Sophie; Nolde, Martin; Hausmann, Dominikus; Lützner, Jörg; Goralski, Szymon; Bassermann, Florian; Spiekermann, Karsten; Hofbauer, Lorenz C.; Schwind, Sebastian; Platzbecker, Uwe; Götze, Katharina; Metzeler, Klaus H.

doi:10.1038/s41375-022-01700-3

Cited by 7 publications

(10 citation statements)

References 25 publications

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“…Next, we investigated the allelic burden of 18 different mutations from 14 patients (7 DNMT3A , 3 ASXL1 , 3 PPM1D , 2 TET2 , 2 CHEK2 , and 1 SF3B1 mutations) in flow‐sorted cell fractions. VAFs were significantly lower in B and T cells compared with monocytes and granulocytes consistent with previous findings 4 , 28 , 29 (Figure 2).…”

Section: Resultssupporting

confidence: 92%

Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients

Panagiota,

Kerschbaum,

Penack

et al. 2023

HemaSphere

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Recent evidence revealed important interactions between clonal hematopoiesis (CH) and cellular therapies established for the treatment of hematologic malignancies. The impact of CH on safety, efficacy, and outcome of chimeric antigen receptor (CAR) T-cell therapy is currently under investigation. We analyzed 110 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (n = 105) or acute lymphoblastic leukemia (ALL) (n = 5), treated with Axicabtagene-Ciloleucel (39%), Tisagenlecleucel (51%), or Brexucabtagene autoleucel (10%). Using error-corrected targeted sequencing, a high CH prevalence of 56.4% (variant allele frequency [VAF] ≥1%) at the time of CAR T-cell infusion was detected. The most frequently mutated gene was PPM1D followed by DNMT3A, TET2, ASXL1, and TP53. Variant allele frequencies were significantly lower in B and T cells compared with monocytes and granulocytes. CH did not increase the risk of CAR T-related toxicities. The incidences of cytokine release syndrome and immune effector-cell-associated neurotoxicity syndrome were similar between CHpos and CHneg patients, regardless of clone size, age, or CAR T product. Prolonged cytopenias were not associated with CH. Best overall response rates (ORRs) were numerically but not significantly higher in CHpos patients (ORR 76.7% versus 62.2%; P = 0.13). Furthermore, CH status did not predict progression-free survival or overall survival. Lastly, sequential analysis showed a modest VAF increase of 1.3% and acquisition of novel mutations within 100 days postinfusion. CH was frequent in large B-cell lymphoma/ALL patients receiving CAR T-cells but did not affect toxicity nor treatment response or outcome.

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Section: Resultssupporting

confidence: 92%

Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients

Panagiota,

Kerschbaum,

Penack

et al. 2023

HemaSphere

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“…However, in this specific case, the consistent differences between pathological samples (myeloid and lymphoid) and saliva during the WES indicated that the latter was at least largely uncontaminated. Rather, the novel SNVs that we identified, since they were mostly not proven to be cancerogenic, might be signs of clonal hemopoiesis rather than being associated with PMF development/progression [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Use of Next Generation Sequencing to Define the Origin of Primary Myelofibrosis

Visani¹,

Etebari

Fuligni

et al. 2023

Cancers

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Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm (MPN) characterized by progressive bone marrow sclerosis, extra-medullary hematopoiesis, and possible transformation to acute leukemia. In the last decade, the molecular pathogenesis of the disease has been largely uncovered. Particularly, genetic and genomic studies have provided evidence of deregulated oncogenes in PMF as well as in other MPNs. However, the mechanisms through which transformation to either the myeloid or lymphoid blastic phase remain obscure. Particularly, it is still debated whether the disease has origins in a multi-potent hematopoietic stem cells or instead in a commissioned myeloid progenitor. In this study, we aimed to shed light upon this issue by using next generation sequencing (NGS) to study both myeloid and lymphoid cells as well as matched non-neoplastic DNA of PMF patients. Whole exome sequencing revealed that most somatic mutations were the same between myeloid and lymphoid cells, such findings being confirmed by Sanger sequencing. Particularly, we found 126/146 SNVs to be the e same (including JAK2V617F), indicating that most genetic events likely to contribute to disease pathogenesis occurred in a non-commissioned precursor. In contrast, only 9/27 InDels were similar, suggesting that this type of lesion contributed instead to disease progression, occurring at more differentiated stages, or maybe just represented “passenger” lesions, not contributing at all to disease pathogenesis. In conclusion, we showed for the first time that genetic lesions characteristic of PMF occur at an early stage of hematopoietic stem cell differentiation, this being in line with the possible transformation of the disease in either myeloid or lymphoid acute leukemia.

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“…Therefore, it is important to realize that our understanding of CH has broadened beyond these initial narrow definitions. First, by using sensitive methods to detect variants in myeloid driver genes at VAFs below the 2% threshold, CH can be detected in over half of persons ≥70 years [ 17 , 21 ]. Second, whole-exome sequencing approaches in large cohorts revealed that CH can also affect driver genes implicated in lymphoid neoplasia, thereby identifying lymphoid CH (L-CH) as a more rare cousin of myeloid (M)-CH [ 22 ].…”

Section: Defining and Detecting The Spectrum Of Chmentioning

confidence: 99%

“…CH may directly or indirectly influence the differentiation capacity and/or function of various hematopoietic cell types, including neutrophils, monocytes, monocyte-derived macrophages, NK cells, B and T cells, as well as other immune-modulatory cells contributing to the osteo-hematopoietic niche, such as megakaryocytes and osteoclasts [ 14 , 26 – 28 ]. Recent studies have shed light on the lineage involvement of the most frequently mutated “DTA” genes [ 21 , 29 , 30 ]. Across these studies, sorted T cells showed a significantly lower allelic burden of mutated “DTA” genes (i.e.…”

Section: Defining and Detecting The Spectrum Of Chmentioning

confidence: 99%

“…Using an improved single-cell sequencing pipeline, the authors showed that monocytes, CD4 + T cells, and NK cells carrying DNMT3A driver mutations present activated gene signatures, which in conjunction with indirect activation of wild-type cells by DNMT3A -mutant macrophages may promote progression of inflammatory reactions in patients [ 31 ]. With regard to ASXL1 -mutant CH, our recent investigation suggests that specific ASXL1 variants may show higher lymphoid compartment (T and B cell) involvement compared to other ASXL1 variants [ 21 ]. These data, while based on a limited number of patients, also demonstrate that different variants for the same gene may show different lineage distribution patterns, adding to the complexity of CH.…”

Section: Defining and Detecting The Spectrum Of Chmentioning

confidence: 99%

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Clonal hematopoiesis and its impact on the aging osteo-hematopoietic niche

Winter,

Götze,

Hecker

et al. 2024

Leukemia

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Clonal hematopoiesis (CH) defines a premalignant state predominantly found in older persons that increases the risk of developing hematologic malignancies and age-related inflammatory diseases. However, the risk for malignant transformation or non-malignant disorders is variable and difficult to predict, and defining the clinical relevance of specific candidate driver mutations in individual carriers has proved to be challenging. In addition to the cell-intrinsic mechanisms, mutant cells rely on and alter cell-extrinsic factors from the bone marrow (BM) niche, which complicates the prediction of a mutant cell’s fate in a shifting pre-malignant microenvironment. Therefore, identifying the insidious and potentially broad impact of driver mutations on supportive niches and immune function in CH aims to understand the subtle differences that enable driver mutations to yield different clinical outcomes. Here, we review the changes in the aging BM niche and the emerging evidence supporting the concept that CH can progressively alter components of the local BM microenvironment. These alterations may have profound implications for the functionality of the osteo-hematopoietic niche and overall bone health, consequently fostering a conducive environment for the continued development and progression of CH. We also provide an overview of the latest technology developments to study the spatiotemporal dependencies in the CH BM niche, ideally in the context of longitudinal studies following CH over time. Finally, we discuss aspects of CH carrier management in clinical practice, based on work from our group and others.

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Compartment-specific mutational landscape of clonal hematopoiesis

Cited by 7 publications

References 25 publications

Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients

Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients

Use of Next Generation Sequencing to Define the Origin of Primary Myelofibrosis

Clonal hematopoiesis and its impact on the aging osteo-hematopoietic niche

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