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1. CDC20 in and out of mitosis: a prognostic factor and therapeutic target in hematological malignancies

Author

Bruno S., Ghelli Luserna di Rora A., Napolitano R., Soverini S., Martinelli G., Simonetti G., Bruno S., Ghelli Luserna di Rora A., Napolitano R., Soverini S., Martinelli G., and Simonetti G.

Subjects
Cancer Research, Cdc20 Protein, Prognosi, Cdc20 Proteins, Apcin, Mitotic checkpoint, Mitosis, CDC20, Cell Cycle Proteins, Mitosi, Prognosis, Oncology, Hematologic Neoplasms, Neoplasms, Cell Cycle Protein, Humans, Hematological malignancie, Hematologic Neoplasm, Human
Abstract

Cell division cycle 20 homologue (CDC20) is a well-known regulator of cell cycle, as it controls the correct segregation of chromosomes during mitosis. Many studies have focused on the biological role of CDC20 in cancer development, as alterations of its functionality have been linked to genomic instability and evidence demonstrated that high CDC20 expression levels are associated with poor overall survival in solid cancers. More recently, novel CDC20 functions have been demonstrated or suggested, including the regulation of apoptosis and stemness properties and a correlation with immune cell infiltration. Here, we here summarize and discuss the role of CDC20 inside and outside mitosis, starting from its network of interacting proteins. In the last years, CDC20 has also attracted more interest in the blood cancer field, being overexpressed and showing an association with prognosis both in myeloid and lymphoid malignancies. Preclinical findings showed that selective CDC20 and APC/CCDC20/APC/CCDH1 inhibitors, namely Apcin and proTAME, are effective against lymphoma and multiple myeloma cells, resulting in mitotic arrest and apoptosis and synergizing with clinically-relevant drugs. The evidence and hypothesis presented in this review provide the input for further biological and chemical studies aiming to dissect novel potential CDC20 roles and targeting strategies in hematological malignancies.

Published
2022

2. The proportion of different BCR-ABL1 transcript types in chronic myeloid leukemia. An international overview

Author

Baccarani, M, Castagnetti, F, Gugliotta, G, Rosti, G, Soverini, S, Albeer, A, Pfirrmann, M, Bekadja, Ma, Entasoltan, B, Nachi, M, Elghandour, A, El Sorady, M, Abdelfattah, R, El Nahass, Y, Samra, M, Azzazi, M, Elsobki, E, Moussa, M, Fahmy, O, Mattar, M, Shehata, Azmy, Se, (Azmy, E, 9 ), Emad), Bolarinwa, (Bolarinwa, Ra, ( 10 ), Rahman A., Eid, (Eid, S, Samir)( 11, ), Khelif, (Khelif, A, Abderrhaim)( 11, ), Hached, (Hached, F, Farhat)( 11, ), Menif, (Menif, S, Samia)( 12, ), Rahman, (Rahman, H, Hafizur)( 13, ), Huang, (Huang, Xj, Xiaojun)(, 14, 15, ), Jiang, (Jiang, Q, Qian)(, 14, (Ye, Yx, Yuanxin)( 16, ), Zhu, (Zhu, Hl, Huanling)( 16, ), Chen, (Chen, Sn, Suning)( 17, ), Varma, (Varma, N, Neelam)( 18, ), Ganesan, (Ganesan, P, Prasanth)( 19, ), Gundeti, (Gundeti, S, Sadashivudu)( 20, ), Malhotra, (Malhotra, H, Hemant)( 21, ), Radhakrishnan, (Radhakrishnan, Vs, ( 22 ), Vivek S., Kumar, (Kumar, L, Lalit)( 23, ), Sharawat, (Sharawat, Sk, Surender Kumar)( 23, ), Seth, (Seth, T, Tulika)( 24, ), Ausekar, (Ausekar, Bv, ( 25 ), B. V., Balasubramanian, (Balasubramanian, P, Poonkuzhali)( 26, ), Poopak, (Poopak, B, Behzad)(, 27, 28, ), Inokuchi, (Inokuchi, K, Koiti)( 29, ), Kim, (Kim, Dw, Dong-Wook)( 30, ), Kindi, Al, S (Al Kindi, Salam)( 31, ), Mirasol, (Mirasol, A, Angelina)( 32, ), Qari, (Qari, M, Mohammed)( 33, ), Goh, (Goh, Yt, Yeow Tee)( 34, ), Shih, (Shih, Ly, Lee-Yung)(, 35, 36, ), Branford, (Branford, S, Susan)(, 37, 38, ), Lion, (Lion, T, Thomas)( 39, ), Valent, (Valent, P, Peter)( 40, ), Burgstaller, (Burgstaller, S, Sonja)( 41, ), Thaler, (Thaler, J, Joseph)( 41, ), Labar, (Labar, B, Boris)( 42, ), Zadro, (Zadro, R, Renata)( 42, ), Mayer, (Mayer, J, Jiri)(, 43, 44, ), Zackova, (Zackova, D, Daniela)(, 43, Faber, (Faber, E, Edgar)( 45, ), Pallisgaard, (Pallisgaard, N, Niels)( 46, ), Xavier-Mahon, (Xavier-Mahon, F, Francois)( 47, ), Lippert, (Lippert, E, Eric)( 48, ), Cayuela, (Cayuela, Jm, Jean Michel)( 49, ), Rea, (Rea, D, Delphine)( 49, ), Millot, (Millot, F, Frederic)( 50, ), Suttorp, (Suttorp, M, Meinolf)( 51, ), Hochhaus, (Hochhaus, A, Andreas)( 52, ), Niederwieser, (Niederwieser, D, Dietger)( 53, ), Saussele, (Saussele, S, Susanne)( 54, ), Haferlach, (Haferlach, T, Torsten)( 55, ), Jeromine, (Jeromine, S, Sabine)( 55, ), Panayiotidis, (Panayiotidis, P, Panayiotis)(, 56, 57, ), Conneally, (Conneally, E, Eibhlin)( 58, ), Langabeer, (Langabeer, S, Steve)( 58, ), Nagler, (Nagler, A, Arnon)(, 59, 60, ), Rupoli, (Rupoli, S, Serena)( 61, ), Santoro, (Santoro, N, Nicola)( 62, ), Albano, (Albano, F, Francesco)( 63, ), Castagnetti, (Castagnetti, F, Fausto), Ottaviani, (Ottaviani, E, Emanuela)(, 64, 65, ), Rambaldi, (Rambaldi, A, Alessandro)(, 66, 67, ), Stagno, (Stagno, F, Fabio)( 68, ), Molica, (Molica, S, Stefano)( 69, ), Biagiotti, (Biagiotti, C, Caterina)( 70, ), Scappini, (Scappini, B, Barbara)( 70, ), Lemoli, (Lemoli, R, Roberto)( 71, ), Iurlo, (Iurlo, A, Alessandra)(, 72, 73, ), Pungolino, (Pungolino, E, Ester)( 74, ), Menna, (Menna, G, Giuseppe), Pane, (Pane, F, Fabrizio)( 76, ), Gottardi, (Gottardi, E, Enrico)(, 77, 78, ), Rege-Cambrin, (Rege-Cambrin, G, Giovanna)(, 77, Binotto, (Binotto, G, Gianni)( 79, ), Putti, (Putti, Mc, Maria Caterina)( 80, ), Falzetti, (Falzetti, F, Franca)( 81, ), Visani, (Visani, G, Giuseppe)( 82, ), Galimberti, (Galimberti, S, Sara)( 83, ), Musto, (Musto, P, Pellegrino)( 84, ), Abruzzese, (Abruzzese, E, Elisabetta)( 85, ), Breccia, (Breccia, M, Massimo)( 86, ), Giona, (Giona, F, Fiorina)( 86, ), Chiusolo, (Chiusolo, P, Patrizia)( 87, ), Sica, (Sica, S, Simona)( 87, ), Fava, (Fava, C, Carmen)( 88, ), Ferrero, (Ferrero, D, Dario)( 88, ), Tiribelli, (Tiribelli, M, Mario)( 89, ), Bonifacio, (Bonifacio, M, Massimiliano)( 90, ), Griskevicius, (Griskevicius, L, Laimonas)( 91, ), Musteata, (Musteata, V, Vasile)( 92, ), Janssen, (Janssen, J, Jeroen)( 93, ), Prejzner, (Prejzner, W, Witold)( 94, ), Sacha, (Sacha, T, Tomasz)( 95, ), Waclaw, (Waclaw, J, Joanna)( 95, ), Almeida, (Almeida, Am, Antonio Medina)( 96, ), Kulikov, (Kulikov, S, Sergei)( 97, ), Turkina, (Turkina, A, Anna)( 97, ), Bogdanovic, (Bogdanovic, A, Andrija)( 98, ), Zupan, (Zupan, I, Irena)( 99, ), Marce, (Marce, S, Silvia)( 100, ), Cervantes, (Cervantes, F, Francisco)( 101, ), Steegmann, (Steegmann, Jl, Juan Luis)( 102, ), Kotlyarchuk, (Kotlyarchuk, K, Konstyantyn)( 103, ), Milner, (Milner, Bj, ( 104 ), Benedict J., Rose, (Rose, S, Susan)( 105, ), Clench, (Clench, T, Tim)( 106, ), Waits, (Waits, P, Paula)( 107, ), Austin, (Austin, S, Steve)( 108, ), Wickham, (Wickham, C, Caroline)( 109, ), Clark, (Clark, R, Richard)( 110, ), Apperley, (Apperley, J, Jane), Claudiani, (Claudiani, S, Simone)( 111, ), Foroni, (Foroni, L, Letizia)( 111, ), Szydlo, (Szydlo, R, Richard)( 111, ), Burt, (Burt, E, Emma)( 112, ), Bescoby, (Bescoby, R, Ruth)( 113, ), Cork, (Cork, L, Leanne)( 113, ), O'Brien, (O'Brien, S, Stephen)( 113, ), Green, (Green, B, Bethaney)( 114, ), Hawtree, (Hawtree, S, Sarah)( 114, ), Watson, (Watson, M, Mark)( 114, ), Bengio, (Bengio, Rm, Raquel Maria)( 115, ), Larripa, (Larripa, I, Irene)( 115, ), Pavlovsky, (Pavlovsky, C, Carolina)( 116, ), Moiraghi, (Moiraghi, B, Beatriz)( 117, ), Pinna, De, CAR (Requiao de Pinna, Cristiane Almeida)( 118, ), Magalhaes, GHR (Romani Magalhaes, Gustavo Henrique)( 119, ), Pagnano, (Pagnano, K, Katia)( 120, ), Funke, (Funke, V, Vaneuza)( 121, ), Tavares, (Tavares, Rs, Renato Sampaio)( 122, ), Prado, (Prado, A, Adriana)( 123, ), Azevedo, (Azevedo, Aa, Alita Andrade)( 124, ), Fogliatto, (Fogliatto, L, Laura)( 125, ), Bonecker, (Bonecker, S, Simone)( 126, ), Centrone, (Centrone, R, Renato)( 127, ), Moellman, (Moellman, A, Artur)( 128, ), Conchon, (Conchon, M, Monika)( 130, ), Centurion, (Centurion, Me, Maria Elida)( 131, ), (Prado, Ai, Ana-Ines)( 132, ), Lopez, (Lopez, Jl, ( 133 ), J. L., Petruzziello, (Petruzziello, F, Fara)( 75, ), Bendit, (Bendit, I, Israel), Baccarani M., Castagnetti F., Gugliotta G., Rosti G., Soverini S., Albeer A., and Pfirrmann M.

Subjects
Male, 0301 basic medicine, Cancer Research, bcr-abl, Fusion Proteins, bcr-abl, Global Health, 0302 clinical medicine, hemic and lymphatic diseases, 80 and over, Odds Ratio, Prevalence, Age Factor, Chronic, Young adult, Child, MOLECULAR RESPONSE, Leukemic, Aged, 80 and over, Leukemia, Hematology, Gene Expression Regulation, Leukemic, CHRONIC MYELOGENOUS LEUKEMIA, Age Factors, Myeloid leukemia, Middle Aged, Oncology, Child, Preschool, 030220 oncology & carcinogenesis, Female, Life Sciences & Biomedicine, Human, Adult, Transcriptional Activation, medicine.medical_specialty, Adolescent, Immunology, IMATINIB MESYLATE, DENDRITIC CELLS, CML PATIENTS, Young Adult, 03 medical and health sciences, Myelogenous, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Internal medicine, medicine, Humans, 1112 Oncology and Carcinogenesis, BCR/ABL TRANSCRIPT, Preschool, CYTOGENETIC RESPONSE, Aged, Science & Technology, CHRONIC-PHASE, business.industry, Infant, Newborn, Fusion Proteins, ABL FUSION PROTEINS, P190 BCR-ABL, Infant, 1103 Clinical Sciences, Odds ratio, Newborn, medicine.disease, International BCR-ABL Study Group, Settore MED/15 - MALATTIE DEL SANGUE, 030104 developmental biology, Imatinib mesylate, Gene Expression Regulation, BCR-ABL Positive, business, Chronic myelogenous leukemia
Abstract

There are different BCR-ABL1 fusion genes that are translated into proteins that are different from each other, yet all leukemogenic, causing chronic myeloid leukemia (CML) or acute lymphoblastic leukemia. Their frequency has never been systematically investigated. In a series of 45503 newly diagnosed CML patients reported from 45 countries, it was found that the proportion of e13a2 (also known as b2a2) and of e14a2 (also known as b3a2), including the cases co-expressing e14a2 and e13a2, was 37.9% and 62.1%, respectively. The proportion of these two transcripts was correlated with gender, e13a2 being more frequent in males (39.2%) than in females (36.2%), was correlated with age, decreasing from 39.6% in children and adolescents down to 31.6% in patients ≥ 80 years old, and was not constant worldwide. Other, rare transcripts were reported in 666/34561 patients (1.93%). The proportion of rare transcripts was associatedwith gender (2.27% in females and 1.69% in males) and with age (from 1.79% in children and adolescents up to 3.84% in patients ≥ 80 years old). These data show that the differences in proportion are not by chance. This is important, as the transcript type is a variable that is suspected to be of prognostic importance for response to treatment, outcome of treatment, and rate of treatment-free remission.

Published
2019
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3. The proportion of different BCR-ABL1 transcript types in chronic myeloid leukemia. An international overview

Author

Baccarani, M, Gugliotta, G, Rosti, G, Soverini, S, Albeer, A, Pfirrmann, M, Bekadja, MA, Entasoltan, B, Nachi, M, Elghandour, A, El Sorady, M, Abdelfattah, R, El Nahass, Y, Samra, M, Azzazi, M, Elsobki, E, Moussa, M, Fahmy, O, Mattar, M, Shehata, SE, Azmy, E, Bolarinwa, RA, Eid, S, Khelif, A, Hached, F, Menif, S, Rahman, H, Huang, XJ, Jiang, Q, Ye, YX, Zhu, HL, Chen, SN, Varma, N, Ganesan, P, Gundeti, S, Malhotra, H, Radhakrishnan, VS, Kumar, L, Sharawat, SK, Seth, T, Ausekar, BV, Balasubramanian, P, Poopak, B, Inokuchi, K, Kim, DW, Al Kindi, S, Mirasol, A, Qari, M, Goh, YT, Shih, LY, Branford, S, Lion, T, Valent, P, Burgstaller, S, Thaler, J, Labar, B, Zadro, R, Mayer, J, Zackova, D, Faber, E, Pallisgaard, N, Xavier-Mahon, F, Lippert, E, Cayuela, JM, Rea, D, Millot, F, Suttorp, M, Hochhaus, A, Niederwieser, D, Saussele, S, Haferlach, T, Jeromine, S, Panayiotidis, P, Conneally, E, Langabeer, S, Nagler, A, Rupoli, S, Santoro, N, Albano, F, Castagnetti, F, Ottaviani, E, Rambaldi, A, Stagno, F, Molica, S, Biagiotti, C, Scappini, B, Lemoli, R, Iurlo, A, Pungolino, E, Menna, G, Pane, F, Gottardi, E, Rege-Cambrin, G, Binotto, G, Putti, MC, Falzetti, F, Visani, G, Galimberti, S, Musto, P, Abruzzese, E, Breccia, M, Giona, F, Chiusolo, P, Sica, S, Fava, C, Ferrero, D, Tiribelli, M, Bonifacio, M, Griskevicius, L, Musteata, V, Janssen, J, Prejzner, W, Sacha, T, Waclaw, J, Almeida, AM, Kulikov, S, Turkina, A, Bogdanovic, A, Zupan, I, Marce, S, Cervantes, F, Steegmann, JL, Kotlyarchuk, K, Milner, BJ, Rose, S, Clench, T, Waits, P, Austin, S, Wickham, C, Clark, R, Apperley, J, Claudiani, S, Foroni, L, Szydlo, R, Burt, E, Bescoby, R, Cork, L, O'Brien, S, Green, B, Hawtree, S, Watson, M, Bengio, RM, Larripa, I, Pavlovsky, C, Moiraghi, B, de Pinna, CAR, Magalhaes, GHR, Pagnano, K, Funke, V, Tavares, RS, Prado, A, Azevedo, AA, Fogliatto, L, Bonecker, S, Centrone, R, Moellman, A, Conchon, M, Centurion, ME, Prado, AI, Lopez, JL, Petruzziello, F, and Bendit, I

Abstract

There are different BCR-ABL1 fusion genes that are translated into proteins that are different from each other, yet all leukemogenic, causing chronic myeloid leukemia (CML) or acute lymphoblastic leukemia. Their frequency has never been systematically investigated. In a series of 45503 newly diagnosed CML patients reported from 45 countries, it was found that the proportion of e13a2 (also known as b2a2) and of e14a2 (also known as b3a2), including the cases co-expressing e14a2 and el 3a2, was 37.9% and 62.1%, respectively. The proportion of these two transcripts was correlated with gender, e13a2 being more frequent in males (39.2%) than in females (36.2%), was correlated with age, decreasing from 39.6% in children and adolescents down to 31.6% in patients >= 80 years old, and was not constant worldwide. Other, rare transcripts were reported in 666/34561 patients (1.93%). The proportion of rare transcripts was associated with gender (2.27% in females and 1.69% in males) and with age (from 1.79% in children and adolescents up to 3.84% in patients >= 80 years old). These data show that the differences in proportion are not by chance. This is important, as the transcript type is a variable that is suspected to be of prognostic importance for response to treatment, outcome of treatment, and rate of treatment-free remission.

Published
2019

4. Achieving a Major Molecular Response at the Time of a Complete Cytogenetic Response (CCgR) Predicts a Better Duration of CCgR in Imatinib-Treated Chronic Myeloid Leukemia Patients

Author

Iacobucci, I, Saglio, Giuseppe, Rosti, G, Testoni, N, Pane, F, Amabile, M, Poerio, A, Soverini, S, Bassi, S, Cilloni, Daniela, Bassan, R, Breccia, M, Lauria, F, Izzo, B, Merante, S, Frassoni, F, Paolini, S, Montefusco, E, Baccarani, M, Martinelli, G, Gimema, Working, PARTY ON CHRONIC MYELOID LEUKEMIA, Iacobucci, I, Saglio, G, Rosti, G, Testoni, N, Pane, Fabrizio, Amabile, M, Poerio, A, Soverini, S, Bassi, S, Cilloni, D, Bassan, R, Breccia, M, Lauria, F, Izzo, Barbara, Merante, S, Frassoni, F, Paolini, S, Montefusco, E, Baccarani, M, Martinelli, G., Iacobucci I, Saglio G, Rosti G, Testoni N, Pane F, Amabile M, Poerio A, Soverini S, Bassi S, Cilloni D, Bassan R, Breccia M, Lauria F, Izzo B, Merante S, Frassoni F, Paolini S, Montefusco E, Baccarani M, and Martinelli G

Subjects
Male, Oncology, Cancer Research, Neoplasm, Residual, Time Factors, Piperazines, hemic and lymphatic diseases, Chronic, CML, MOLECULAR RESPONSE, Leukemia, Reverse Transcriptase Polymerase Chain Reaction, Remission Induction, CHRONIC MYELOGENOUS LEUKEMIA, Myeloid leukemia, Middle Aged, Prognosis, MINIMAL-RESIDUAL-DISEASE, INTERFERON-ALPHA THERAPY, FUSION GENE TRANSCRIPTS, CHRONIC-PHASE, REMISSION, CYTARABINE, SURVIVAL, MESYLATE, Treatment Outcome, Residual, Predictive value of tests, Benzamides, Imatinib Mesylate, Female, medicine.drug, Adult, medicine.medical_specialty, Endpoint Determination, Antineoplastic Agents, Genes, abl, IMATINIB, Myelogenous, Predictive Value of Tests, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Internal medicine, medicine, Humans, neoplasms, CYTOGENETIC RESPONSE, Aged, CHRONIC MYELOID LEUKEMIA, business.industry, abl, Cytogenetics, Imatinib, medicine.disease, Clinical trial, Pyrimidines, Imatinib mesylate, Genes, Immunology, Neoplasm, BCR-ABL Positive, beta 2-Microglobulin, business
Abstract

Purpose: Most patients with chronic-phase chronic myeloid leukemia (CML) who receive imatinib achieve a complete cytogenetic remission (CCgR) and low levels of BCR-ABL transcripts. CCgR is durable in the majority of patients but relapse occurs in a subset. Experimental Design: To determine the potential of quantitative reverse transcription-PCR of BCR-ABL to predict cytogenetic relapse, we serially monitored residual disease in 97 CML patients with an imatinib-induced CCgR. Patients with late chronic phase CML after IFN-α failure were treated with imatinib (400 mg daily). Results: During the imatinib median follow-up time of 36 months (range, 12-54 months), disease monitoring occurred by cytogenetics and quantitative PCR. Twenty percent of patients experienced cytogenetic relapse at a median of 18 months after CCgR and a median of 24 months after starting imatinib. None of the possible prognostic factors studied in univariate and multivariate analyses seemed to predict for loss of cytogenetic response but the reduction of BCR-ABL transcript levels at the time of CCgR is an important prognostic factor. Conclusions: In our study, we showed not only that achieving a major molecular remission at 12 months is predictive of a durable cytogenetic remission but also that patients who achieved a major molecular remission (expressed both as the BCR-ABL/β2 microglobulin ratio %

Published
2006
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5. Denaturing-HPLC-Based Assay for Detection of ABL Mutations in Chronic Myeloid Leukemia Patients Resistant to Imatinib

Author

SOVERINI S, MARTINELLI G, AMABILE M, POERIO A, BIANCHINI M, ROSTI G, PANE, FABRIZIO, SAGLIO G, BACCARANI M, ITALIAN COOERATIVE STUDY GROUP ON CHRONIC MYELOID LEUKEMIA, EUROPEAN LEUKEMIANET TH FRAMEWORK PROGRAM OF THE EUROPEAN C.O.M.M.U.N.I.T.Y., Soverini, S, Martinelli, G, Amabile, M, Poerio, A, Bianchini, M, Rosti, G, Pane, Fabrizio, Saglio, G, Baccarani, M, ITALIAN COOERATIVE STUDY GROUP ON CHRONIC MYELOID, Leukemia, EUROPEAN LEUKEMIANET TH FRAMEWORK PROGRAM OF THE EUROPEAN, C. O. M. M. U. N. I. T. Y., SOVERINI S, MARTINELLI G., AMABILE M, POERIO A, BIANCHINI M, ROSTI G, PANE F, SAGLIO G, and BACCARANI M.

Subjects
Abelson kinase, medicine.drug_class, DNA Mutational Analysis, Clinical Biochemistry, Fusion Proteins, bcr-abl, Antineoplastic Agents, Genes, abl, Biology, Sensitivity and Specificity, Piperazines, Tyrosine-kinase inhibitor, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, hemic and lymphatic diseases, medicine, Humans, Point Mutation, phosphotransferase, Kinase activity, Chromatography, High Pressure Liquid, Retrospective Studies, ABL, Reverse Transcriptase Polymerase Chain Reaction, Point mutation, Biochemistry (medical), Myeloid leukemia, Imatinib, nucleotide, Protein-Tyrosine Kinases, medicine.disease, acetonitrile, Leukemia, Pyrimidines, Imatinib mesylate, imatinib, Drug Resistance, Neoplasm, Benzamides, Imatinib Mesylate, Cancer research, amino acid, medicine.drug
Abstract

Background: Despite the efficacy of the BCR-ABL tyrosine kinase inhibitor Imatinib mesylate for the treatment of chronic myeloid leukemia (CML), resistance has been observed in a proportion of cases, especially those with advanced stages of the disease. Point mutations within the ABL kinase domain are emerging as the most frequent mechanism for reactivation of kinase activity within the leukemic clone. Methods: We developed a denaturing-HPLC (D-HPLC)-based assay for screening for ABL point mutations. For each sample, two partially overlapping fragments of 393 and 482 bp corresponding to the kinase domain were amplified by nested reverse transcription-PCR and analyzed under selected temperature and acetonitrile gradient conditions. Fifty-one bone marrow and/or peripheral blood specimens from 27 CML patients who showed cytogenetic resistance to Imatinib were screened in parallel by D-HPLC and by direct sequencing. Results: In 12 of 27 (44%) patients, D-HPLC showed an abnormal elution profile suggesting the presence of a nucleotide change. Direct sequencing confirmed the presence of a point mutation in all cases. Conversely, all samples scored as wild type by D-HPLC showed no evidence of mutations by direct sequencing. In two cases, novel amino acid substitutions at codons already known for being hot-spots of mutation were identified (F311I and E355D). Conclusions: The proposed D-HPLC-based assay is highly specific and at least as sensitive as sequencing; with respect to the latter, it provides a much faster and less expensive semiautomated system for mutational screening. It may therefore potentially be a valuable tool for regular, large-scale testing of patients undergoing Imatinib treatment.

Published
2004
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6. What are the challenges in 2016 regarding resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and cancer?

Author

Lewis, M, Copland, M, Soverini, S, Sadovnik, I, Bedel, A, Prost, S, Italiano, A, Mahon, Fx., Lewis, M, Copland, M, Soverini, S, Sadovnik, I, Bedel, A, Prost, S, Italiano, A, and Mahon, Fx.

Subjects
chronic myeloid leukemia, hemic and lymphatic diseases, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, tyrosine kinase inhibitors, Humans, leukemic stem cell, History, 21st Century, Protein Kinase Inhibitors, resistance to treatment
Abstract

In the past decade, the treatment of chronic myeloid leukemia (CML) has undergone a drastic evolution. The discovery and success of imatinib and second-generation tyrosine kinase inhibitors have substantially increased the outcome for CML patients. The next step in medical and scientific research is to better understand the malignancy so as to eventually find a cure to eliminate all leukemic cells from patients. One of the key issues is about the resistance of the leukemic stem cells to tyrosine kinase inhibitors. Here, we briefly describe our current studies on CML resistance, and leukemic stem cell modeling and characterization.

Published
2016

7. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia

Author

Foà, R, Vitale, A, Vignetti, M, Meloni, G, Guarini, A, De Propris MS, Elia, L, Paoloni, F, Fazi, P, Cimino, G, Nobile, F, Ferrara, F, Castagnola, C, Sica, S, Leoni, P, Zuffa, E, Fozza, C, Luppi, Mario, Candoni, A, Iacobucci, I, Soverini, S, Mandelli, F, Martinelli, G, Baccarani, M, GIMEMA Acute Leukemia Working Party, Foà R, Vitale A, Vignetti M, Meloni G, Guarini A, De Propris MS, Elia L, Paoloni F, Fazi P, Cimino G, Nobile F, Ferrara F, Castagnola C, Sica S, Leoni P, Zuffa E, Fozza C, Luppi M, Candoni A, Iacobucci I, Soverini S, Mandelli F, Martinelli G, and Baccarani M.

Subjects
Male, Time Factors, bcr-abl, Dasatinib, Fusion Proteins, bcr-abl, Kaplan-Meier Estimate, Biochemistry, Gastroenterology, Immunophenotyping, Recurrence, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Young adult, BCR-ABL inhibitor, Leukemic, acute lymphoblastic leukemia, Gene Expression Regulation, Leukemic, Reverse Transcriptase Polymerase Chain Reaction, Remission Induction, Myeloid leukemia, Hematology, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Flow Cytometry, Debulking, CD, ACUTE LYMPHOBLASTIC LEUKEMIA (ALL), Treatment Outcome, Female, Steroids, medicine.drug, Adult, medicine.medical_specialty, Immunology, Philadelphia chromosome, Drug Administration Schedule, Young Adult, Antigens, CD, Internal medicine, medicine, Humans, Antigens, Protein Kinase Inhibitors, Aged, business.industry, Fusion Proteins, Imatinib, Cell Biology, medicine.disease, Surgery, Settore MED/15 - MALATTIE DEL SANGUE, Thiazoles, Pyrimidines, Imatinib mesylate, Gene Expression Regulation, Multivariate Analysis, business
Abstract

Dasatinib is a potent BCR-ABL inhibitor effective in chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia (ALL) resistant/intolerant to imatinib. In the GIMEMA LAL1205 protocol, patients with newly diagnosed Ph+ ALL older than 18 years (with no upper age limit) received dasatinib induction therapy for 84 days combined with steroids for the first 32 days and intrathecal chemotherapy. Postremission therapy was free. Fifty-three patients were evaluable (median age, 53.6 years). All patients achieved a complete hematologic remission (CHR), 49 (92.5%) at day 22. At this time point, 10 patients achieved a BCR-ABL reduction to < 10−3. At 20 months, the overall survival was 69.2% and disease-free survival was 51.1%. A significant difference in DFS was observed between patients who showed at day 22 a decrease in BCR-ABL levels to < 10−3 compared with patients who never reached these levels during induction. In multivariate analysis, BCR-ABL levels of < 10−3 at day 85 correlated with disease-free survival. No deaths or relapses occurred during induction. Twenty-three patients relapsed after completing induction. A T315I mutation was detected in 12 of 17 relapsed cases. Treatment was well tolerated; only 4 patients discontinued therapy during the last phase of the induction when already in CHR. In adult Ph+ ALL, induction treatment with dasatinib plus steroids is associated with a CHR in virtually all patients, irrespective of age, good compliance, no deaths, and a very rapid debulking of the neoplastic clone. This trial was registered at [www.clinicaltrials.gov][1] as #[NCT00391989][2]. [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00391989&atom=%2Fbloodjournal%2F118%2F25%2F6521.atom

Published
2011
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8. A population-based study of chronic myeloid leukemia patients treated with imatinib in first line

Author

Castagnetti, F, DI RAIMONDO, Francesco, De Vivo, A, Spitaleri, A, Gugliotta, G, Fabbiano, F, Capodanno, I, Mannina, D, Salvucci, M, Antolino, A, Marasca, R, Musso, M, Crugnola, M, Impera, S, Trabacchi, E, Musolino, C, Cavazzini, F, Mineo, G, Tosi, P, Tomaselli, C, Rizzo, M, Siragusa, S, Fogli, M, Ragionieri, R, Zironi, A, Soverini, S, Martinelli, G, Cavo, M, Vigneri, Paolo, Stagno, F, Rosti, G, Baccarani, M., Castagnetti, Fausto, Di Raimondo, Francesco, De Vivo, Antonio, Spitaleri, Antonio, Gugliotta, Gabriele, Fabbiano, Francesco, Capodanno, Isabella, Mannina, Donato, Salvucci, Marzia, Antolino, Agostino, Marasca, Roberto, Musso, Maurizio, Crugnola, Monica, Impera, Stefana, Trabacchi, Elena, Musolino, Caterina, Cavazzini, Francesco, Mineo, Giuseppe, Tosi, Patrizia, Tomaselli, Carmela, Rizzo, Michele, Siragusa, Sergio, Fogli, Miriam, Ragionieri, Riccardo, Zironi, Alessandro, Soverini, Simona, Martinelli, Giovanni, Cavo, Michele, Vigneri, Paolo, Stagno, Fabio, Rosti, Gianantonio, and Baccarani, Michele

Subjects
Male, Leukemia, Chronic myeloid leukemia, Hematology, Middle Aged, Disease-Free Survival, NO, Hematology, Chronic myeloid leukemia, imatinib, Disease-Free Survival, Female, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Male, Middle Aged, Prospective Studies, Protein Kinase Inhibitors, Treatment Outcome, Treatment Outcome, imatinib, Female, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Prospective Studies, Protein Kinase Inhibitors, BCR-ABL Positive, Chronic, Myelogenous
Abstract

Chronic myeloid leukemia (CML) treatment is based on company-sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first-line therapy. These studies included patients selected according to many inclusion–exclusion criteria, particularly age and comorbidities, with specific treatment obligations. In daily clinical practice (real-life), inclusion–exclusion criteria do not exist, and the treatment outcome does not only depend on the choice of first-line TKI but also on second- and third-line TKIs. To investigate in a real-life setting the response and the outcome on first-line imatinib, with switch to second generation TKIs in case of unsatisfying response or intolerance, we analyzed all newly diagnosed patients (N = 236), living in two Italian regions, registered in a prospective study according to population-based criteria and treated front-line with imatinib. A switch from imatinib to second-generation TKIs was reported in 14% of patients for side effects and in 24% for failure or suboptimal response, with an improvement of molecular response in 57% of them. The 5-year overall survival (OS) and leukemia-related survival (LRS) were 85% and 93%, respectively; the 4-year rates of MR3.0 and MR4.0 were 75% and 48%, respectively. Cardiovascular complications were reported in 4% of patients treated with imatinib alone and in 6% of patients receiving nilotinib as second-line. Older age (≥70 years) affected OS, but not LRS. These data provide an unbiased reference on the CML management and on the results of TKI treatment in real-life, according to ELN recommendations, using imatinib as first-line treatment and second-generation TKIs as second-line therapy. Am. J. Hematol. 92:82–87, 2017. © 2016 Wiley Periodicals, Inc.

Published
2016

9. IMATINIB FIRST-LINE WITH SWITCH TO 2ND GENERATION TYROSINE KINASE INHIBITORS IN CASE OF FAILURE OR TOXICITY: REAL-LIFE DATA FROM A POPULATION-BASED REGISTRY OF BCR-ABL1+CML PATIENTS

Author

Castagnetti, F., Stagno, F., de Vivo, A., Spitalieri, A., Gugliotta, G., Fabbiano, F., Capodanno, I., Mannina, D., Salvucci, M., Antolino, A., Marasca, R., Musso, M., Crugnola, M., Consoli, U., Trabacchi, E., Musolino, C., Cavazzini, Francesco, Longo, G., Tosi, P., Cardinale, G., Soverini, S., Rizzo, M., Martinelli, G., Cavo, M., Vigneri, P., Rosti, G., Di Raimondo, F., and Baccarani, M.

Subjects
Socio-culturale
Published
2016

11. Deep Molecular Response to Nilotinib As First-Line Treatment of BCR-ABL plus CML in Early Chronic Phase: A Phase 3b Multicenter Study of the Gimema CML Working Party

Author

Castagnetti, F, Gugliotta, G, Breccia, M, Martino, B, Rossi, G, Stagno, F, Turri, D, Tiribelli, M, Trabacchi, E, Isidori, A, Pierri, I, Leonardi, G, Pregno, P, Carella, Am, Bochicchio, Mt, Testoni, N, Soverini, S, Specchia, G, Alimena, G, Cavo, M, Martinelli, G, Pane, F, Saglio, G, Baccarani, M, and Rosti, G

Published
2014

12. DECLINING ROLE OF DISEASE TRANSORMATION AS A CAUSE OF DEATH IN CHRONIC MYELOID LEUKEMIA TREATED WITH IMATINIB IN EARLY CHRONIC PHASE: A LONG-TERM ANALYSIS BY THE GIMEMA CML WP

Author

Castagnetti, F., Gugliotta, G., Breccia, M., Specchia, G., Intermesoli, T., Iurlo, A., Martino, B., Binotto, G., Cavazzini, F., Abruzzese, E., Stagno, F., Leoni, P., Ferrero, D., Rege-Cambrin, G., Bocchia, M., Gherlinzoni, F., FRANCESCA PALANDRI, Soverini, S., Alimena, G., Pane, F., Martinelli, G., Cavo, M., Saglio, G., Baccarani, M., and Rosti, G.

Published
2014

14. Updating Long-Term Outcome of Intermittent Imatinib (INTERIM) Treatment in Elderly Patients with Ph plus -CML

Author

Russo, D, Martinelli, G, Malagola, M, Cancelli, V, Skert, C, Soverini, S, Iacobucci, I, Turri, D, Mirto, S, Gobbi, M, Pierri, I, Vitolo, U, Pregno, P, Fogli, M, Testoni, N, De Vivo, A, Castagnetti, F, Morra, E, Pungolino, E, Di Raimondo, F, Stagno, F, Alimena, G, Breccia, M, Nobile, F, Martino, B, Rambaldi, A, Intermesoli, T, Saglio, G, Cambrin, Gr, Visani, G, Nicolini, G, de Fabritiis, P, Abruzzese, E, Fanin, R, Tiribelli, M, Galieni, P, Bigazzi, C, Specchia, G, Angelucci, E, Usala, E, Musolino, C, Russo, S, Gaidano, G, Lunghi, M, Lauria, F, Bocchia, M, Rodeghiero, F, D'Emilio, A, Bosi, A, Santini, V, Quarta, G, Girasoli, M, Fioritoni, G, Di Lorenzo, R, Cesana, Bm, and Rosti, G

Published
2014

15. SEVEN YEAR-EXPERIENCE OF BCR-ABL MUTATION ANALYSIS IN PHILADELPHIA-CHROMOSOME POSITIVE (PH+) PATIENTS ON IMATINIB (IM) OR 2ND-GENERATION TYROSINE KINASE INHIBITORS (TKIS): BY THE GIMEMA CML WORKING PARTY

Author

Soverini, S, Gnani, A, De Benedittis, C, Castagnetti, F, Gugliotta, G, Breccia, M, Pregno, P, Abruzzese, E, Sorà, F, Baratè, C, Gangemi, D, Capucci, A, Girasoli, M, Orlandi, E, Specchia, G, Russo, D, Giannini, B, Poletti, G, Iacobucci, I, Bochicchio, T, Pane, F, Saglio, G, Rosti, G, Baccarani, M, and Martinelli, G

Published
2011

21. MOLECULAR CHARACTERIZATION OF TP53 MUTATIONS IN B-ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL) REVEALS MISSENSE SUBSTITUTIONS, ABERRANT EXON-JUNCTIONS AND INTRON RETENTION EVENTS

Author

Iacobucci, I., Ferrari, A., Lonetti, A., CRISTINA PAPAYANNIDIS, Trino, S., Venturi, C., Ferrarini, A., Venturini, L., Abbenante, M., Parisi, S., Cattina, F., Soverini, S., Russo, D., Vignetti, M., Pane, F., Delledonne, M., Baccarani, M., Martinelli, G., Iacobucci I, Ferrari A, Lonetti A, Papayannidis C, Trino S, Venturi C, Ferrarini A, Venturini L, Abbenante MC, Parisi S, Cattina F, Soverini S, Russo D, Vignetti M, Pane F, Delledonne M, Baccarani M, and Martinelli G.

Subjects
ACUTE LYMPHOBLASTIC LEUKEMIA (ALL), TP53

22. Real-time quantification of different types of bcr-abl transcript in chronic myeloid leukemia

Author

Amabile, M., Giannini, B., Testoni, N., Montefusco, V., Rosti, G., Zardini, C., CAROLINA TERRAGNA, Buonamici, S., Ottaviani, E., Soverini, S., Fiacchini, M., Bassi, S., Vivo, A., Trabacchi, E., Saglio, G., Pane, F., Baccarani, M., Tura, S., Martinelii, G., Amabile, M., Giannini, B., Testoni, N., Montefusco, V., Rosti, G., Zardini, C., Terragna, C., Buonamici, S., Ottaviani, E., Soverini, S., Fiacchini, M., Bassi, S., DE VIVO, A., Trabacchi, E., Saglio, G., Pane, Fabrizio, Baccarani, M., Tura, S., and Martinelli, G.

Subjects
Male, Leukemia, Reverse Transcriptase Polymerase Chain Reaction, Messenger, abl, Genes, abl, Sensitivity and Specificity, Genes, Bone Marrow, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Methods, RNA, Humans, BCR-ABL Positive, Female, RNA, Messenger, Chronic, Myelogenous
Abstract

The most common translocation in chronic myeloid leukemia (CML) t(9;22) (q34;q22) produces the BCR/ABL fusion gene. We set up and evaluated a rapid and reliable real-time reverse-transcription-polymerase chain reaction (RT-PCR) approach using TaqMan technology for detection and quantification of bcr-abl transcripts in CML patients at diagnosis and during therapy.A pair of primers and probe complementary to ABL exon 2 were designed, enabling detection of the most frequent bcr-abl transcripts, and also of the normal ABL-Ia transcript as an internal control. Conditions were established to amplify less than 1(-10) target molecules/reaction and detect one CML cell in 10(6) cells from healthy donors. To determine the utility of the assay, we quantified the bcr-abl/ABL-Ia ratio in 59 bone marrow samples (45 samples with evidence of different Ph+ chromosome percentages and 14 samples in complete cytogenetic remission) from 48 CML patients, 34 of them at diagnosis and 14 in clinical remission (CR). In 14 cases, this ratio was compared with results obtained by a competitive-quantitative RT-PCR/capillary electrophoresis method from contemporary specimens.By real-time RT-PCR, the median value of bcr-abl/ABL-Ia ratio at diagnosis was 15.334 (range 3.3-28.81) and fell to 0.9 (range 0.003-26.1) in CR. The median value of bcr-abl/ABL-Ia ratio at cytogenetic remission was 0.7 (range 0.003-2.83). The real-time bcr-abl/ABL-Ia ratios correlated with those obtained by competitive RT-PCR (p0.0001) and the percentage of Ph+ metaphases (p0.0001). The high sensitivity and specificity of the real-time RT-PCR procedure was confirmed in all 14 patients with minimal residual disease. INTERPRETATION AND CONCLUSIONS. We conclude that this real-time RT-PCR procedure is a reliable and sensitive method of monitoring CML patients after therapy, and that the bcr-abl/ABL-Ia ratio correlates strongly with cytogenetic analysis.

23. Thyrosin kinase inhibitors: Nilotinib

Author

Castagnetti, F., Palandri, F., Gugliotta, G., Poerio, A., Marilina Amabile, Soverini, S., Martinelli, G., Baccarani, M., Rosti, G., Castagnetti F., Palandri F., Gugliotta G., Poerio A., Amabile M., Soverini S., Martinelli G., Baccarani M., and Rosti G.

Subjects
NILOTINIB, CHRONIC MYELOID LEUKEMIA (CML)

24. DEEP SEQUENCING OF THE BCR-ABL KINASE DOMAIN REVEALS A FREQUENCY OF 35INS INSERTION/TRUNCATION HIGHER THAN EXPECTED

Author

Benedittis, C., Soverini, S., Polakova, K., Brouckova, A., Castagnetti, F., Gugliotta, G., FRANCESCA PALANDRI, Papayannidis, C., Klamova, H., Bresciani, P., Coluccio, V., Salvucci, M., Tiribelli, M., Intermesoli, T., Binotto, G., Iacobucci, I., Venturi, C., Luppi, M., Ottaviani, E., Bochicchio, M., Cattina, F., Manuela, M., Leo, E., Haferlach, T., Kohlmann, A., Russo, D., Rosti, G., Baccarani, M., Cavo, M., Martinelli, G., and De Benedittis C, Soverini S, Machova Polakova K, Brouckova A, Castagnetti F, Gugliotta G, Palandri F, Papayannidis C, Klamova H, Bresciani P, Coluccio V, Salvucci M, Tiribelli M, Binotto G, Intermesoli T, Iacobucci I, Venturi C, Luppi M, Ottaviani E, MT Bochicchio, Cattina F, Mancini M, Elisa L, Haferlach T, Kohlmann A, Russo D, Rosti G, Baccarani M, Cavo M, Martinelli G.

Subjects
Philadelphia-positive Leukemia, drug-resistance, hemic and lymphatic diseases, Bcr-Abl kinase domain mutation, BCR-ABL, deep-amplicon sequencing, deletion, BCR-ABL 35INS, deep-amplicon sequencing, BCR-ABL, TKI, resistance to tyrosine kinase inhibitor, insertion
Abstract

Background: The spectrum of Bcr-Abl kinase domain mechanisms that confer resistance to tyrosine kinase inhibitors (TKIs) in Philadelphia-positive (Ph+) Leukemia is quite heterogeneous. Not always molecular events underlying drug-resistance can be explained by presence of mutations; Bcr-Abl KD insertions/deletions can be an alternative mutational mechanisms. The recent development of “deep-amplicon sequencing” (DS) technologies has opened the way to a more accurate characterization of molecular aberrations in Ph+ Leukemia with higher sensitivity of screening for know and unknown mutations. Aims: We took advantage of a DS approach in order to fully characterize the spectrum of insertions and deletions in CML and Ph+ ALL patients who had developed resistance to one or multiple lines of TKI therapy. Methods: We set up a Bcr-Abl KD mutation screening assay on the Roche GS Junior instrument that allows to reliably detect sequence variants and deletions or insertions with a lower detection limit of 1%. A total of 67 samples from 26 CML and 13 Ph+ ALL patients who had developed resistance to one or multiple TKIs (Imatinib, Dasatinib, Nilotinib) were selected for this analysis. In order to reconstruct the dynamics of growth of mutations we evaluated their presence in a serial follow-up samples collected during TKI therapy in 6 patients. Results: DS revealed a 35-base insertion (35INS) in 18/26 (69%) CML and 11/13 (84%) ALL Ph+ patients with an abundance from 1% up to 96% of all BcrAbl transcripts. Interestingly DS highlighted an increased expression of 35INS over time in 6 patients (growth ranged from 2% to 96% within a few months). This insertion is known to retain a stop codon which causes the loss of 653 Cterminal amino acids of Bcr-Abl resulting in early termination and a truncated Bcr-Abl1 protein missing a significant portion of the C-terminal regulatory regions. In addition DS detected 2 in-frame deletions in 3 samples, with an abundance from 2% to 19% . This not previously described variants include a 72-nt deletion (1233-1304) between the junction of Abl exon 6 and 7 that causes the loss of 24 amino acids (aa 359-383) and a 42-nt deletion in exon 7 (1258-1299) which leads to loss of 14 amino acids (aa 371-384). Summary / Conclusion: Our results show that DS technologies on the GS Junior instrument allow a more accurate characterization of mutational status of patients in comparison to conventional sequencing methods. The higher sensitivity of DS approach allowed to highlight, both in CML and in Ph ALL+ patients, a frequency of 35INS higher than previously reported (60%). The 35INS thus seems to be very frequent in CML and Ph+ ALL patients who develop resistance to one or multiple lines of TKI therapies but its abundance is dynamic in individual patients and seems not to be related to TKI therapy. In line with our results, recent 35INS in vitro studies have demonstrated that this insertion is kinase-inactive and should not contribute to TKI-resistance. Although this insertion does not predict for a specific TKIs-resistance its role in Ph+ Leukemia merit additional studies and further analysis of a larger number of samples will be needed to better understand its biological and clinical relevance

25. Nilotinib: a novel encouraging therapeutic option for chronic myeloid leukemia patients with imatinib resistance or intolerance

Author

Martinelli, G., Iacobucci, I., Soverini, S., FRANCESCA PALANDRI, Castagnetti, F., Rosti, G., Baccarani, M., Martinelli G., Iacobucci I., Soverini S., Palandri F., Castagnetti F., Rosti G., and Baccarani M.

Subjects
hemic and lymphatic diseases, Chronic myeloid leukemia, Review, Imatinib resistance, Nilotinib, neoplasms, CHRONIC MYELOID LEUKEMIA (CML)
Abstract

Although high rates of complete hematologic and cytogenetic remission have been observed in patients with chronic phase chronic myeloid leukemia (CML) treated with imatinib, a short duration of response with eventual emergence of imatinib resistance has also been reported in a subset of CML patients. The most frequent clinically relevant mechanisms that change imatinib sensitivity in BCR-ABL-transformed cells are mutations within the Abl kinase domain, affecting several of its properties. Crystal structure analysis of the Abl-imatinib complex has proven helpful in identifying potential critical residues that hinder interactions of imatinib with mutated Abl. This has led to the development of a second generation of targeted therapies such as nilotinib and dasatinib, already in phase II clinical trials or SKI-606 and MK-0457 in phase I trials. In this review, we discuss the activity of nilotinib, developed by Novartis using a rational drug design strategy in which imatinib served as the lead compound. Preliminary studies demonstrated that nilotinib has more efficacy than imatinib in inhibiting proliferation of BCR-ABL-dependent cells, a relatively safety profile and clinical efficacy in all phases of CML.

26. AT THE TIME OF DIAGNOSIS, PH+ CELLS FROM BOTH CHRONIC PHASE CHRONIC MYELOID LEUKEMIA AND ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS ALREADY HARBOUR BCR-ABL KINASE DOMAIN MUTATIONS

Author

Soverini, S., Poerio, A., Vitale, A., Gnani, A., Colarossi, S., Castagnetti, F., Iacobucci, I., Lonetti, A., FRANCESCA PALANDRI, Rosti, G., Amabile, M., Paolini, S., Papayannidis, C., Gugliotta, G., Vignetti, M., Mandelli, F., Baccarani, M., Foa, R., Martinelli, G., Soverini S, Poerio A, Vitale A, Gnani A, Colarossi S, Castagnetti F., Iacobucci I, Lonetti A, Palandri F, Rosti G, Amabile M, Paolini S, Papayannidis C, Gugliotta G, Vignetti M, Mandelli F, Baccarani M, Foà R, and Martinelli G

Subjects
acute lymphoblastic leukemia (ALL), hemic and lymphatic diseases, chronic myeloid leukemia (CML)
Abstract

Background and Aims. Mutations in the Bcr-Abl kinase domain (KD) are often detected at the time of resistance to tyrosine kinase inhibitor (TKI) therapy in Philadelphia-positive (Ph+) leukemias. Mutations in rare Ph+ cells have been detected in some imatinib-naïve advanced-phase chronic myeloid leukemia (CML) patients (pts), but it is still unclear whether and with what incidence low level mutations may already be detectable at the time of diagnosis in Ph+ acute lymphoblastic leukemia (ALL) pts and in chronic-phase (CP) chronic myeloid leukemia pts. We therefore analyzed cDNA samples from 24 newly diagnosed pts with Ph+ ALL (n=13) or CP-CML (n=11) who subsequently received TKI therapy (imatinib, dasatinib or nilotinib). Methods. Screening for low level mutations was performed by cloning the Bcr-Abl KD (a.a. 206-524) in a bacterial vector and sequencing 200 independent clones for each pt. Results. All pts had evidence of aberrant KD sequences. Three to twelve different mutations were detected in each pt. Each mutation was present in two to five independent clones. A total of 115 mutations (including 41 silent, 5 nonsense, and 69 missense mutations) were observed. The vast majority (107/115, 93%) have never been reported in association with TKI resistance and are likely not to confer any advantage under TKI selective pressure. Interestingly, 103/115 (90%) mutations were transitions: G>A (n=30), A>G (n=25), C>T (n=25), T>C (n=23). Such a high prevalence of transitions (normally occurring 1.4 times more frequently than transversions) suggests that a specific mechanism generating mutations is active in Ph+ cells (activation- induced cytidine deaminase?). One of the eleven CP-CML pt received hydroxyurea for 6 months before starting imatinib therapy. In this pt, high-sensitivity mutation screening was performed again immediately before imatinib start and showed further accumulation of mutations. Eight Ph+ ALL pts and three CML pts subsequently relapsed with evidence of mutations, but only two with a mutation (T315I) that was already detectable at diagnosis. The remaining thirteen pts are in persistent remission after a follow up ranging from 12 to 52 months, although four of them were harbouring known imatinib-(H396P, D276G, E355G) or dasatinib-(F317L) resistant mutations at low levels. Conclusions. Our observations suggest that: a) Bcr-Abl KD mutations can probably be found at diagnosis in all CP-CML and Ph+ ALL pts; b) mutations seem to arise randomly and most of them are silent or not conferring any growth advantage under the selective pressure of TKIs; c) generation of mutations seems to be linked to Bcr-Abl-driven genetic instability; d) TKI-resistant mutations present at low levels at diagnosis do not always outgrow and lead to relapse, probably because some of them arise in cell clones with limited self-renewal capacity. This warns against high-sensitivity mutation screening of all CML and Ph+ ALL pts before the start of TKI therapy.

32. High rate of complete hematological response in elderly Ph+ acute lymphoblastic leukemia (ALL) patients by innovative sequential use of nilotinib and imatinib: a GIMEMA clinical trial LAL 1408

Author

Papayannidis, C., Piciocchi, A., Vitale, A., Soverini, S., Benedittis, C., Iacobucci, I., Paolini, S., Sartor, C., Abbenante, M., Di Raimondo, F., Massimiliano BONIFACIO, Carella, Am, Cazzola, M., Cuneo, A., Leoni, P., Luppi, M., Morra, E., Specchia, G., Vallisa, D., Bocchia, M., Fanin, R., Saglio, G., Elia, L., Foà, R., Cavo, M., Baccarani, M., and Martinelli, G.

Subjects
imatinib, complete remission, Philadelphia-positiva, Acute Lymphoblastic Leukemia, Philadelphia-positiva, nilotinib, imatinib, complete remission, Acute Lymphoblastic Leukemia, nilotinib

35. HIGH RATE OF COMPLETE HEMATOLOGICAL RESPONSE IN ELDERLY PH plus ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) PATIENTS BY INNOVATIVE SEQUENTIAL USE OF NILOTINIB AND IMATINIB: A GIMEMA CLINICAL TRIAL LAL 1408

Author

CRISTINA PAPAYANNIDIS, Piciocchi, A., Vitale, A., Soverini, S., Benedittis, C., Iacobucci, I., Paolini, S., Sartor, C., Abbenante, M., Di Raimondo, F., Bonifacio, M., Carella, A. M., Cazzola, M., Cuneo, A., Leoni, P., Luppi, M., Morra, E., Specchia, G., Vallisa, D., Bocchia, M., Fanin, R., Saglio, G., Elia, L., Foa, R., Cavo, M., Baccarani, M., and Martinelli, G.

36. GAS1 AND KIF27 GENES ARE STRONGLY UP-REGULATED BIOMARKERS OF HEDGEHOG INHIBITION (PF-04449913) ON LEUKEMIA STEM CELLS IN PHASE I ACUTE MYELOID LEUKEMIA AND CHRONIC MYELOID LEUKEMIA TREATED PATIENTS

Author

Guadagnuolo, V., CRISTINA PAPAYANNIDIS, Iacobucci, I., Durante, S., Terragna, C., Ottaviani, E., Cattina, F., Abbenante, M., Soverini, S., Toni, L., Levin, W., Courtney, R., Baldazzi, C., Curti, A., Baccarani, M., Jamieson, C., Cortes, J., Oehler, V., Mclachlan, K., Arsdale, T., Martinelli, G., V Guadagnuolo, C Papayannidi, I Iacobucci, S Durante, C Terragna, E Ottaviani, F Cattina, M Abbenante, S Soverini, L Toni, W Levin, R Courtney, C Baldazzi, A Curti, M Baccarani, C Jamieson, J Corte, V Oehler, K McLachlan, T Van Arsdale, and G Martinelli

Subjects
ACUTE MYELOID LEUKEMIA, HEDGEHOG INHIBITION, CHRONIC MYELOID LEUKEMIA (CML)

41. HIGH SENSITIVITY MUTATION SCREENING AND CLONAL ANALYSIS ALLOWED BY ULTRA-DEEP AMPLICON SEQUENCING UNCOVER THE COMPLEXITY OF BCR-ABL MUTATION STATUS IN PATIENTS TREATED WITH TYROSINE KINASE INHIBITORS

Author

Soverini, S., Benedittis, C., Cattina, F., Brouckova, A., Polakova, K. Machova, Russo, D., Gnani, A., Iacobucci, I., Bochicchio, M. T., Castagnetti, F., Gugliotta, G., FRANCESCA PALANDRI, Papayannidis, C., Klamova, H., Vitale, A., Vignetti, M., Foa, R., Rosti, G., Baccarani, M., Martinelli, G., S Soverini, C De Beneditti, F Cattina, A Broucková, K Machová Poláková, D Russo, A Gnani, I Iacobucci, MT Bochicchio, F Castagnetti, G Gugliotta, F Palandri, C Papayannidi, H Klamová, A Vitale, M Vignetti, R Foà, G Rosti, M Baccarani, and G Martinelli

Subjects
TKI

43. CLINICAL SIGNIFICANCE OF EARLY MOLECULAR RESPONSE IN CHRONIC MYELOID LEUKEMIA PATIENTS TREATED FRONTLINE WITH IMATINIB MESYLATE

Author

Castagnetti, F., Gugliotta, G., Breccia, M., Albano, F., Abruzzese, E., Levato, L., Cavazzini, F., Lurlo, A., Stagno, F., Ferrero, D., Porretto, F., Martino, B., Rupoli, S., Intermesoli, T., Fava, C., Pierri, I., FRANCESCA PALANDRI, Venturi, C., Soverini, S., Luatti, S., Alimena, G., Pane, F., Martinelli, G., Saglio, G., Cavo, M., Baccarani, M., and Rosti, G.

50. Different isoforms of the B-cell mutator activation-induced cytidine deaminase are aberrantly expressed in BCR–ABL1-positive acute lymphoblastic leukemia patients

Author

Sabina Chiaretti, Emanuela Ottaviani, Antonella Vitale, Marco Vignetti, Francesca Messa, Monica Messina, Stefania Paolini, Daniela Cilloni, Fabrizio Pane, Robert Foa, Ilaria Iacobucci, Simona Soverini, Francesca Paoloni, Giorgio Berton, Giuseppe Saglio, Cristina Papayannidis, Michele Baccarani, Anna Baruzzi, Alberto Ferrari, Giovanni Martinelli, Francesca Arruga, Annalisa Lonetti, Pier Paolo Piccaluga, Iacobucci I, Lonetti A, Messa F, Ferrari A, Cilloni D, Soverini S, Paoloni F, Arruga F, Ottaviani E, Chiaretti S, Messina M, Vignetti M, Papayannidis C, Vitale A, Pane F, Piccaluga PP, Paolini S, Berton G, Baruzzi A, Saglio G, Baccarani M, Foà R, Martinelli G., Iacobucci, I, Lonetti, A, Messa, F, Ferrari, A, Cilloni, D, Soverini, S, Paoloni, F, Arruga, F, Ottaviani, E, Chiaretti, S, Messina, M, Vignetti, M, Papayannidis, C, Vitale, A, Pane, Fabrizio, Piccaluga, Pp, Paolini, S, Berton, G, Baruzzi, A, Saglio, G, Baccarani, M, Foà, R, and Martinelli, G.

Subjects
Cancer Research, analysis, bcr-abl, Messenger, B-CELL, Fusion Proteins, bcr-abl, analysis/genetics, Exon, Single-Stranded, hemic and lymphatic diseases, Activation-induced (cytidine) deaminase, genetics, dasatinib, genetics/physiology, all, Genes, Immunoglobulin, enzymology/genetics, aid, bcr-abl1, class switch recombination, chronic myeloid leukemia, somatic hypermutation, lymphocytic leukemia, adult, probabilities, monotherapy, mechanism, breakpoint cluster region, Hematology, Cytidine deaminase, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, Isoenzymes, medicine.anatomical_structure, Oncology, BCR-ABL1-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS, Adult, Gene isoform, Adolescent, Somatic hypermutation, Biology, Cytidine Deaminase, Immunoglobulin, medicine, Humans, DNA Breaks, Single-Stranded, RNA, Messenger, B cell, Aged, DNA Breaks, Fusion Proteins, Alternative Splicing, Genes, RNA, Immunoglobulin class switching, biology.protein, Cancer research
Abstract

The main reason for the unfavorable clinical outcome of BCR-ABL1-positive acute lymphoblastic leukemia (ALL) is genetic instability. However, how normal B-cell precursors acquire the genetic changes that lead to transformation has not yet been completely defined. We investigated the expression of the activation-induced cytidine deaminase (AID) and its role in clinical outcome in 61 adult BCR-ABL1-positive ALL patients. AID expression was detected in 36 patients (59%); it correlated with the BCR-ABL1 transcript levels and disappeared after treatment with tyrosine kinase inhibitors. Different AID splice variants were identified: full-length isoform; AIDDeltaE4a, with a 30-bp deletion of exon 4; AIDDeltaE4, with the exon 4 deletion; AIDins3, with the retention of intron 3; AIDDeltaE3-E4 isoform without deaminase activity. AID-FL predominantly showed cytoplasmic localization, as did the AID-DeltaE4a and AID-DeltaE3E4 variants, whereas the C-terminal-truncated AID-DeltaE4 showed a slightly increased nuclear localization pattern. AID expression correlated with a higher number of copy number alterations identified in genome-wide analysis using a single-nucleotide polymorphism array. However, the expression of AID at diagnosis was not associated with a worse prognosis. In conclusion, BCR-ABL1-positive ALL cells aberrantly express different isoforms of AID that may act as mutators outside the immunoglobulin (Ig) gene loci in promoting genetic instability.

Published
2009
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