Effects of miRNA-15 and miRNA-16 expression replacement in chronic lymphocytic leukemia: implication for therapy

G. Cutrona; S. Matis; M. Colombo; C. Massucco; G. Baio; F. Valdora; L. Emionite; S. Fabris; A. G. Recchia; M. Gentile; C. E. Neumaier; D. Reverberi; R . Massara; S. Boccardo; L. Basso; S. Salvi; F. Rosa; M. Cilli; S. Zupo; M. Truini; P. Tassone; M. Calabrese; M. Negrini; A. Neri; F. Morabito; F. Fais; M. Ferrarini

doi:10.1038/leu.2016.394

Effects of miRNA-15 and miRNA-16 expression replacement in chronic lymphocytic leukemia: implication for therapy

G. Cutrona, S. Matis, M. Colombo, C. Massucco, G. Baio, F. Valdora, L. Emionite, S. Fabris, A. G. Recchia, M. Gentile, C. E. Neumaier, D. Reverberi, R . Massara, S. Boccardo, L. Basso, S. Salvi, F. Rosa, M. Cilli, S. Zupo, M. TruiniP. Tassone, M. Calabrese, M. Negrini, A. Neri, F. Morabito, F. Fais, M. Ferrarini

Applied Medicine

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Abstract

Chronic lymphocytic leukemia (CLL) clones are characterized by loss of a critical region in 13q14.3, (del(13)(q14)) involving the microRNA (miRNA) cluster miR-15a and miR-16-1. We have investigated the effects of replacement of miR-15a and miR-16-1. CLL cells transfected with these miRNA mimics exhibited a decrease in cell viability in vitro and impaired capacity for engraftment and growth in NOD/Shi-scid,γcnull (NSG) mice. No synergistic effects were observed when the two miRNA mimics were combined. The phenomena were not restricted to CLL with the del(13)(q14) lesion. Similar effects induced by miRNA mimics were seen in cells with additional chromosomal abnormalities with the exception of certain CLL clones harboring TP53 alterations. Administration of miRNA mimics to NSG mice previously engrafted with CLL clones resulted in substantial tumor regression. CLL cell transfection with miR-15a and miR-16-1-specific inhibitors resulted in increased cell viability in vitro and in an enhanced capacity of the engrafted cells to grow in NSG mice generating larger splenic nodules. These data demonstrate that the strong control by miR-15a and miR-16-1 on CLL clonal expansion is exerted also at the level of full-blown leukemia and provide indications for a miRNA-based therapeutic strategy.

Original language	English
Pages (from-to)	1894-1904
Number of pages	11
Journal	Leukemia
Volume	31
Issue number	9
Early online date	5 Jan 2017
DOIs	https://doi.org/10.1038/leu.2016.394
Publication status	Published - Sept 2017

Bibliographical note

This work was supported by: Associazione Italiana Ricerca sul Cancro (AIRC) Grant 5 x mille n.9980, (to M.F., F.M. A. N., P.T. and M.N.) ; AIRC I.G. n. 14326 (to M.F.), n.10136 and 16722 (A.N.), n.15426 (to F.F.). AIRC and Fondazione CaRiCal co-financed Multi Unit Regional Grant 2014 n.16695 (to F.M.). Italian Ministry of Health 5x1000 funds (to S.Z. and F.F). A.G R. was supported by Associazione Italiana contro le Leucemie-Linfomi-Mielomi (AIL) Cosenza - Fondazione Amelia Scorza (FAS). S.M. C.M., M.C., L.E., S.B. were supported by AIRC.

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Cutrona, G., Matis, S., Colombo, M., Massucco, C., Baio, G., Valdora, F., Emionite, L., Fabris, S., Recchia, A. G., Gentile, M., Neumaier, C. E., Reverberi, D., Massara, R. ., Boccardo, S., Basso, L., Salvi, S., Rosa, F., Cilli, M., Zupo, S., ... Ferrarini, M. (2017). Effects of miRNA-15 and miRNA-16 expression replacement in chronic lymphocytic leukemia: implication for therapy. Leukemia, 31(9), 1894-1904. https://doi.org/10.1038/leu.2016.394

Cutrona, G, Matis, S, Colombo, M, Massucco, C, Baio, G, Valdora, F, Emionite, L, Fabris, S, Recchia, AG, Gentile, M, Neumaier, CE, Reverberi, D, Massara, R, Boccardo, S, Basso, L, Salvi, S, Rosa, F, Cilli, M, Zupo, S, Truini, M, Tassone, P, Calabrese, M, Negrini, M, Neri, A, Morabito, F, Fais, F & Ferrarini, M 2017, 'Effects of miRNA-15 and miRNA-16 expression replacement in chronic lymphocytic leukemia: implication for therapy', Leukemia, vol. 31, no. 9, pp. 1894-1904. https://doi.org/10.1038/leu.2016.394

@article{1e520949205441e78c3d80e09bfc4261,

title = "Effects of miRNA-15 and miRNA-16 expression replacement in chronic lymphocytic leukemia: implication for therapy",

abstract = "Chronic lymphocytic leukemia (CLL) clones are characterized by loss of a critical region in 13q14.3, (del(13)(q14)) involving the microRNA (miRNA) cluster miR-15a and miR-16-1. We have investigated the effects of replacement of miR-15a and miR-16-1. CLL cells transfected with these miRNA mimics exhibited a decrease in cell viability in vitro and impaired capacity for engraftment and growth in NOD/Shi-scid,γcnull (NSG) mice. No synergistic effects were observed when the two miRNA mimics were combined. The phenomena were not restricted to CLL with the del(13)(q14) lesion. Similar effects induced by miRNA mimics were seen in cells with additional chromosomal abnormalities with the exception of certain CLL clones harboring TP53 alterations. Administration of miRNA mimics to NSG mice previously engrafted with CLL clones resulted in substantial tumor regression. CLL cell transfection with miR-15a and miR-16-1-specific inhibitors resulted in increased cell viability in vitro and in an enhanced capacity of the engrafted cells to grow in NSG mice generating larger splenic nodules. These data demonstrate that the strong control by miR-15a and miR-16-1 on CLL clonal expansion is exerted also at the level of full-blown leukemia and provide indications for a miRNA-based therapeutic strategy.",

author = "G. Cutrona and S. Matis and M. Colombo and C. Massucco and G. Baio and F. Valdora and L. Emionite and S. Fabris and Recchia, {A. G.} and M. Gentile and Neumaier, {C. E.} and D. Reverberi and Massara, {R .} and S. Boccardo and L. Basso and S. Salvi and F. Rosa and M. Cilli and S. Zupo and M. Truini and P. Tassone and M. Calabrese and M. Negrini and A. Neri and F. Morabito and F. Fais and M. Ferrarini",

note = "This work was supported by: Associazione Italiana Ricerca sul Cancro (AIRC) Grant 5 x mille n.9980, (to M.F., F.M. A. N., P.T. and M.N.) ; AIRC I.G. n. 14326 (to M.F.), n.10136 and 16722 (A.N.), n.15426 (to F.F.). AIRC and Fondazione CaRiCal co-financed Multi Unit Regional Grant 2014 n.16695 (to F.M.). Italian Ministry of Health 5x1000 funds (to S.Z. and F.F). A.G R. was supported by Associazione Italiana contro le Leucemie-Linfomi-Mielomi (AIL) Cosenza - Fondazione Amelia Scorza (FAS). S.M. C.M., M.C., L.E., S.B. were supported by AIRC.",

year = "2017",

month = sep,

doi = "10.1038/leu.2016.394",

language = "English",

volume = "31",

pages = "1894--1904",

journal = "Leukemia",

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TY - JOUR

T1 - Effects of miRNA-15 and miRNA-16 expression replacement in chronic lymphocytic leukemia

T2 - implication for therapy

AU - Cutrona, G.

AU - Matis, S.

AU - Colombo, M.

AU - Massucco, C.

AU - Baio, G.

AU - Valdora, F.

AU - Emionite, L.

AU - Fabris, S.

AU - Recchia, A. G.

AU - Gentile, M.

AU - Neumaier, C. E.

AU - Reverberi, D.

AU - Massara, R .

AU - Boccardo, S.

AU - Basso, L.

AU - Salvi, S.

AU - Rosa, F.

AU - Cilli, M.

AU - Zupo, S.

AU - Truini, M.

AU - Tassone, P.

AU - Calabrese, M.

AU - Negrini, M.

AU - Neri, A.

AU - Morabito, F.

AU - Fais, F.

AU - Ferrarini, M.

N1 - This work was supported by: Associazione Italiana Ricerca sul Cancro (AIRC) Grant 5 x mille n.9980, (to M.F., F.M. A. N., P.T. and M.N.) ; AIRC I.G. n. 14326 (to M.F.), n.10136 and 16722 (A.N.), n.15426 (to F.F.). AIRC and Fondazione CaRiCal co-financed Multi Unit Regional Grant 2014 n.16695 (to F.M.). Italian Ministry of Health 5x1000 funds (to S.Z. and F.F). A.G R. was supported by Associazione Italiana contro le Leucemie-Linfomi-Mielomi (AIL) Cosenza - Fondazione Amelia Scorza (FAS). S.M. C.M., M.C., L.E., S.B. were supported by AIRC.

PY - 2017/9

Y1 - 2017/9

N2 - Chronic lymphocytic leukemia (CLL) clones are characterized by loss of a critical region in 13q14.3, (del(13)(q14)) involving the microRNA (miRNA) cluster miR-15a and miR-16-1. We have investigated the effects of replacement of miR-15a and miR-16-1. CLL cells transfected with these miRNA mimics exhibited a decrease in cell viability in vitro and impaired capacity for engraftment and growth in NOD/Shi-scid,γcnull (NSG) mice. No synergistic effects were observed when the two miRNA mimics were combined. The phenomena were not restricted to CLL with the del(13)(q14) lesion. Similar effects induced by miRNA mimics were seen in cells with additional chromosomal abnormalities with the exception of certain CLL clones harboring TP53 alterations. Administration of miRNA mimics to NSG mice previously engrafted with CLL clones resulted in substantial tumor regression. CLL cell transfection with miR-15a and miR-16-1-specific inhibitors resulted in increased cell viability in vitro and in an enhanced capacity of the engrafted cells to grow in NSG mice generating larger splenic nodules. These data demonstrate that the strong control by miR-15a and miR-16-1 on CLL clonal expansion is exerted also at the level of full-blown leukemia and provide indications for a miRNA-based therapeutic strategy.

AB - Chronic lymphocytic leukemia (CLL) clones are characterized by loss of a critical region in 13q14.3, (del(13)(q14)) involving the microRNA (miRNA) cluster miR-15a and miR-16-1. We have investigated the effects of replacement of miR-15a and miR-16-1. CLL cells transfected with these miRNA mimics exhibited a decrease in cell viability in vitro and impaired capacity for engraftment and growth in NOD/Shi-scid,γcnull (NSG) mice. No synergistic effects were observed when the two miRNA mimics were combined. The phenomena were not restricted to CLL with the del(13)(q14) lesion. Similar effects induced by miRNA mimics were seen in cells with additional chromosomal abnormalities with the exception of certain CLL clones harboring TP53 alterations. Administration of miRNA mimics to NSG mice previously engrafted with CLL clones resulted in substantial tumor regression. CLL cell transfection with miR-15a and miR-16-1-specific inhibitors resulted in increased cell viability in vitro and in an enhanced capacity of the engrafted cells to grow in NSG mice generating larger splenic nodules. These data demonstrate that the strong control by miR-15a and miR-16-1 on CLL clonal expansion is exerted also at the level of full-blown leukemia and provide indications for a miRNA-based therapeutic strategy.

U2 - 10.1038/leu.2016.394

DO - 10.1038/leu.2016.394

M3 - Article

SN - 0887-6924

VL - 31

SP - 1894

EP - 1904

JO - Leukemia

JF - Leukemia

IS - 9

ER -

Effects of miRNA-15 and miRNA-16 expression replacement in chronic lymphocytic leukemia: implication for therapy

Abstract

Bibliographical note

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