Although intratumor heterogeneity has been inferred in multiple myeloma (MM), little is known about its subclonal phylogeny. To describe such phylogenetic trees in a series of patients with MM, we perform whole-exome sequencing and single-cell genetic analysis. Our results demonstrate that at presentation myeloma is composed of two to six different major clones, which are related by linear and branching phylogenies. Remarkably, the earliest myeloma-initiating clones, some of which only had the initiating t(11;14), were still present at low frequencies at the time of diagnosis. For the first time in myeloma, we demonstrate parallel evolution whereby two independent clones activate the RAS/MAPK pathway through RAS mutations and give rise subsequently to distinct subclonal lineages. We also report the co-occurrence of RAS and interferon regulatory factor 4 (IRF4) p.K123R mutations in 4% of myeloma patients. Lastly, we describe the fluctuations of myeloma subclonal architecture in a patient analyzed at presentation and relapse and in NOD/SCID-IL2Rγ(null) xenografts, revealing clonal extinction and the emergence of new clones that acquire additional mutations. This study confirms that myeloma subclones exhibit different survival properties during treatment or mouse engraftment. We conclude that clonal diversity combined with varying selective pressures is the essential foundation for tumor progression and treatment resistance in myeloma.

Single-cell genetic analysis reveals the composition of initiating clones and phylogenetic patterns of branching and parallel evolution in myeloma / Melchor L;Brioli A;Wardell CP;Murison A;Potter NE;Kaiser MF;Fryer RA;Johnson DC;Begum DB;Hulkki Wilson S;Vijayaraghavan G;Titley I;Cavo M;Davies FE;Walker BA;Morgan GJ. - In: LEUKEMIA. - ISSN 0887-6924. - STAMPA. - 28:(2014), pp. 1705-1715. [10.1038/leu.2014.13]

Single-cell genetic analysis reveals the composition of initiating clones and phylogenetic patterns of branching and parallel evolution in myeloma.

BRIOLI, ANNAMARIA;CAVO, MICHELE;
2014

Abstract

Although intratumor heterogeneity has been inferred in multiple myeloma (MM), little is known about its subclonal phylogeny. To describe such phylogenetic trees in a series of patients with MM, we perform whole-exome sequencing and single-cell genetic analysis. Our results demonstrate that at presentation myeloma is composed of two to six different major clones, which are related by linear and branching phylogenies. Remarkably, the earliest myeloma-initiating clones, some of which only had the initiating t(11;14), were still present at low frequencies at the time of diagnosis. For the first time in myeloma, we demonstrate parallel evolution whereby two independent clones activate the RAS/MAPK pathway through RAS mutations and give rise subsequently to distinct subclonal lineages. We also report the co-occurrence of RAS and interferon regulatory factor 4 (IRF4) p.K123R mutations in 4% of myeloma patients. Lastly, we describe the fluctuations of myeloma subclonal architecture in a patient analyzed at presentation and relapse and in NOD/SCID-IL2Rγ(null) xenografts, revealing clonal extinction and the emergence of new clones that acquire additional mutations. This study confirms that myeloma subclones exhibit different survival properties during treatment or mouse engraftment. We conclude that clonal diversity combined with varying selective pressures is the essential foundation for tumor progression and treatment resistance in myeloma.
2014
Single-cell genetic analysis reveals the composition of initiating clones and phylogenetic patterns of branching and parallel evolution in myeloma / Melchor L;Brioli A;Wardell CP;Murison A;Potter NE;Kaiser MF;Fryer RA;Johnson DC;Begum DB;Hulkki Wilson S;Vijayaraghavan G;Titley I;Cavo M;Davies FE;Walker BA;Morgan GJ. - In: LEUKEMIA. - ISSN 0887-6924. - STAMPA. - 28:(2014), pp. 1705-1715. [10.1038/leu.2014.13]
Melchor L;Brioli A;Wardell CP;Murison A;Potter NE;Kaiser MF;Fryer RA;Johnson DC;Begum DB;Hulkki Wilson S;Vijayaraghavan G;Titley I;Cavo M;Davies FE;Walker BA;Morgan GJ
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/396660
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