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Leukemia. 2015 May;29(5):1186-94. doi: 10.1038/leu.2014.321. Epub 2014 Nov 12.

Phenotypic identification of subclones in multiple myeloma with different chemoresistant, cytogenetic and clonogenic potential.

Author information

1
1] Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer/Consejo Superior de Investigaciones Científicas-Universidad de Salamanca (IBMCC, USAL-CSIC), Salamanca, Spain [2] Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
2
Clínica Universidad de Navarra, Centro de Investigaciones Médicas Aplicadas (CIMA), Pamplona, Spain.
3
1] Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain [2] Servicio General de Citometría y Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain.
4
Servicio General de Citometría y Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain.
5
Centro do Sangue e da Transplantação de Coimbra, Instituto Português do Sangue e da Transplantação, Coimbra, Portugal.
6
Hospital Universitario de Salamanca, Salamanca, Spain.
7
1] Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer/Consejo Superior de Investigaciones Científicas-Universidad de Salamanca (IBMCC, USAL-CSIC), Salamanca, Spain [2] Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain [3] Hospital Universitario de Salamanca, Salamanca, Spain.
8
1] Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain [2] Hospital Universitario de Salamanca, Salamanca, Spain.
9
Hospital Germans Trias i Pujol, Badalona, Spain.
10
Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain.
11
Hospital de Donostia, San Sebastian, Spain.
12
Hospital Clínic, IDIBAPS, Salamanca, Spain.
13
Hospital 12 de Octubre, Madrid, Spain.

Abstract

Knowledge about clonal diversity and selection is critical to understand multiple myeloma (MM) pathogenesis, chemoresistance and progression. If targeted therapy becomes reality, identification and monitoring of intraclonal plasma cell (PC) heterogeneity would become increasingly demanded. Here we investigated the kinetics of intraclonal heterogeneity among 116 MM patients using 23-marker multidimensional flow cytometry (MFC) and principal component analysis, at diagnosis and during minimal residual disease (MRD) monitoring. Distinct phenotypic subclones were observed in 35/116 (30%) newly diagnosed MM patients. In 10/35 patients, persistent MRD was detected after 9 induction cycles, and longitudinal comparison of patient-paired diagnostic vs MRD samples unraveled phenotypic clonal tiding after therapy in half (5/10) of the patients. After demonstrating selection of distinct phenotypic subsets by therapeutic pressure, we investigated whether distinct fluorescence-activated cell-sorted PC subclones had different clonogenic and cytogenetic profiles. In half (5/10) of the patients analyzed, distinct phenotypic subclones showed different clonogenic potential when co-cultured with stromal cells, and in 6/11 cases distinct phenotypic subclones displayed unique cytogenetic profiles by interphase fluorescence in situ hybridization, including selective del(17p13). Collectively, we unravel potential therapeutic selection of preexisting diagnostic phenotypic subclones during MRD monitoring; because phenotypically distinct PCs may show different clonogenic and cytogenetic profiles, identification and follow-up of unique phenotypic-genetic myeloma PC subclones may become relevant for tailored therapy.

PMID:
25388955
DOI:
10.1038/leu.2014.321
[Indexed for MEDLINE]

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