title: Association between B-cell receptor responsiveness and disease progression in B-cell chronic lymphocytic leukemia: results from single cell network profiling studies.
abstract: While many prognostic markers in B-cell chronic lymphocytic leukemia provide insight into the biology of the disease, few have been demonstrated to be useful in the daily management of patients. B-cell receptor signaling is a driving event in the progression of B-cell chronic lymphocytic leukemia and markers of B-cell receptor responsiveness have been shown to be of prognostic value. Single cell network profiling, a multiparametric flow cytometry-based assay, allows functional signaling analysis at the level of the single cell. B-cell receptor signaling proteins (i.e. p-SYK, p-NF-κB p65, p-ERK, p-p38, p-JNK) were functionally characterized by single cell network profiling in samples from patients with B-cell chronic lymphocytic leukemia in an exploratory study (n=27) after stimulation with anti-IgM. Significant associations of single cell network profiling data with clinical outcome (i.e. time to first treatment), as assessed by Cox regression models, were then confirmed in patients' samples in two other sequential independent studies, i.e. test study 1 (n=30), and test study 2 (n=37). In the exploratory study, higher responsiveness of the B-cell receptor signaling proteins to anti-IgM was associated with poor clinical outcomes. Patients' clustering based on signaling response was at least as powerful in discriminating different disease courses as traditional prognostic markers. In an unselected subgroup of patients with Binet stage A disease (n=21), increased anti-IgM-modulated p-ERK signaling was shown to be a significant, independent predictor of shorter time to first treatment. This result was independently confirmed in two test cohorts from distinct populations of patients. In conclusion, these findings support the utility of the single cell network profiling assay in elucidating signaling perturbations with the potential for the development of a clinically useful prognostic test in patients with early stage B-cell chronic lymphocytic leukemia. These data support the clinical relevance of B-cell receptor signaling in B-cell chronic lymphocytic leukemia, and suggest a key role of ERK activation in the physiopathology of this leukemia.
authors.affiliation: Nodality Inc., South San Francisco, CA, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cesano
authors.forename: Omar
authors.initials: O
authors.lastname: Perbellini
authors.forename: Erik
authors.initials: E
authors.lastname: Evensen
authors.forename: Charles C
authors.initials: CC
authors.lastname: Chu
authors.forename: Federica
authors.initials: F
authors.lastname: Cioffi
authors.forename: Jason
authors.initials: J
authors.lastname: Ptacek
authors.forename: Rajendra N
authors.initials: RN
authors.lastname: Damle
authors.forename: Roberto
authors.initials: R
authors.lastname: Chignola
authors.forename: James
authors.initials: J
authors.lastname: Cordeiro
authors.forename: Xiao-jie
authors.initials: XJ
authors.lastname: Yan
authors.forename: Rachael E
authors.initials: RE
authors.lastname: Hawtin
authors.forename: Ilaria
authors.initials: I
authors.lastname: Nichele
authors.forename: Jodi R
authors.initials: JR
authors.lastname: Ware
authors.forename: Chiara
authors.initials: C
authors.lastname: Cavallini
authors.forename: Ornella
authors.initials: O
authors.lastname: Lovato
authors.forename: Roberta
authors.initials: R
authors.lastname: Zanotti
authors.forename: Kanti R
authors.initials: KR
authors.lastname: Rai
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pizzolo
authors.forename: Maria T
authors.initials: MT
authors.lastname: Scupoli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D002478:Cells, Cultured; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry / Q000379:methods / Q000706:statistics & numerical data; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016328:NF-kappa B / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D059010:Single-Cell Analysis / Q000379:methods*; D000072377:Syk Kinase
chemical_list: D000888:Antibodies, Anti-Idiotypic; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell; C044203:anti-IgM; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D048049:Extracellular Signal-Regulated MAP Kinases