The immune microenvironment shapes transcriptional and genetic heterogeneity in chronic lymphocytic leukemia
Sun, Clare (Hematology Branch. National Heart. Lung. and Blood Institute. National Institutes of Health, Bethesda)
Chen, Yun Ching (Bioinformatics and Computational Biology Core. National Heart. Lung. and Blood Institute. National Institutes of Health, Bethesda)
Zurita, Aina Martinez (Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA)
Baptista, Maria Joao (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Pittaluga, Stefania (Laboratory of Pathology. National Cancer Institute. National Institutes of Health, Bethesda)
Liu, Delong (Bioinformatics and Computational Biology Core. National Heart. Lung. and Blood Institute. National Institutes of Health, Bethesda)
Rosebrock, Daniel (Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge MA)
Gohil, Satyen Harish (University College London)
Saba, Nakhle S. (Tulane University, New Orleans, LA)
Davies-Hill, Theresa (Laboratory of Pathology. National Cancer Institute. National Institutes of Health, Bethesda)
Herman, Sarah E.M. (Hematology Branch. National Heart. Lung. and Blood Institute. National Institutes of Health, Bethesda)
Getz, Gad (Harvard Medical School, Boston, MA)
Pirooznia, Mehdi (Bioinformatics and Computational Biology Core. National Heart. Lung. and Blood Institute. National Institutes of Health, Bethesda)
Wu, Catherine J. (righam and Women's Hospital (Boston, Estats Units d'Amèrica))
Wiestner, Adrian (Hematology Branch. National Heart. Lung. and Blood Institute. National Institutes of Health, Bethesda)

Data:	2023
Resum:	In chronic lymphocytic leukemia (CLL), B-cell receptor signaling, tumor-microenvironment interactions, and somatic mutations drive disease progression. To better understand the intersection between the microenvironment and molecular events in CLL pathogenesis, we integrated bulk transcriptome profiling of paired peripheral blood (PB) and lymph node (LN) samples from 34 patients. Oncogenic processes were upregulated in LN compared with PB and in immunoglobulin heavy-chain variable (IGHV) region unmutated compared with mutated cases. Single-cell RNA sequencing (scRNA-seq) distinguished 3 major cell states: quiescent, activated, and proliferating. The activated subpopulation comprised only 2. 2% to 4. 3% of the total tumor bulk in LN samples. RNA velocity analysis found that CLL cell fate in LN is unidirectional, starts in the proliferating state, transitions to the activated state, and ends in the quiescent state. A 10-gene signature derived from activated tumor cells was associated with inferior treatment-free survival (TFS) and positively correlated with the proportion of activated CD4 memory T cells and M2 macrophages in LN. Whole exome sequencing (WES) of paired PB and LN samples showed subclonal expansion in LN in approximately half of the patients. Since mouse models have implicated activation-induced cytidine deaminase in mutagenesis, we compared AICDA expression between cases with and without clonal evolution but did not find a difference. In contrast, the presence of a T-cell inflamed microenvironment in LN was associated with clonal stability. In summary, a distinct minor tumor subpopulation underlies CLL pathogenesis and drives the clinical outcome. Clonal trajectories are shaped by the LN milieu, where T-cell immunity may contribute to suppressing clonal outgrowth. The clinical study is registered at clinicaltrials. gov as NCT00923507.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Blood advances, Vol. 7 Núm. 1 (january 2023) , p. 145-158, ISSN 2473-9537

DOI: 10.1182/bloodadvances.2021006941
PMID: 35358998

14 p, 3.0 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Institut de Recerca contra la Leucèmia Josep Carreras
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