Loss of CDKN2A, encoding p16/INK4A and p14/ARF tumor suppressors, has been associated with poorer survival and higher leukemia-initiating- cell-frequency in xenograft models (Notta F et al. Nature 2011). Recently, using genome-wide single nucleotide polymorphisms arrays and gene candidate deep exon sequencing, we identified CDKN2A deletions in 29% (29/101) adult newly diagnosed Ph+ ALL patients and in 47% relapsed cases. Accordingly, here we aimed to investigate the functional consequences of genomic deletions and their prognostic value. By quantitative real-time PCR a significant difference in the expression of CDKN2A was observed among cases with heterozygous (p = 0.04) and homozygous (p = 0.01) loss compared to normal cases, suggesting that deletions lead to CDKN2A haploinsufficiency. In order to investigate their clinical implications, data were collected from 81 patients (median follow-up: 25.2 months- range 2.1-148.1; median age at diagnosis: 54 years- range, 18-76; CDKN2A loss in 29, 36%, cases). 72 patients (89%) were enrolled in the GIMEMA clinical trials (12 patients in GIMEMA LAL0201-B protocol, 13 in LAL2000 and 47 in LAL1205 protocols), while 9 patients (11%) were enrolled into institutional protocols. By univariate analysis a shorter overall survival (OS) and disease-free survival (DFS) were found in patients with CDKN2A deletion compared with those wild-type (OS: 27.7 v 38.2 months, respectively, p = 0.0206; DFS: 10.1 vs 56.1 months, respectively, p = 0.0010). Moreover, a higher cumulative incidence of relapse for patients with CDKN2A deletion (73.3 vs 38.1; p = 0.0014) was also recognized. The multivariate analysis confirmed the negative prognostic impact of CDKN2A deletion on DFS (p = 0051). These results show that there are genetically distinct Ph+ ALL patients with a different risk of leukemia relapse and that testing for CDKN2A alterations at diagnosis may help in risk stratification. Furthermore, since the loss of CDKN2A eliminates the critical tumor surveillance mechanism and allows proliferation, cell growth and tumor formation by the action of MDM2 and CDK4/6, attractive drugs to prevent disease recurrence could be represented by the inhibitors of MDM2 and CDK4/ CDK6. These drugs are currently under investigation in in vitro studies by our group. Supported by: ELN, AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2008, Ateneo RFO grants, Project of integreted program, Programma di Ricerca Regione – Università 2007 – 2009.
Iacobucci I, Ferrari A, Papayannidis C, Lonetti A, Paoloni F, Trino S, et al. (2011). LOSS OF CDKN2A GENE IS A POOR PROGNOSTIC MARKER IN ADULT BCR-ABL1 POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) PATIENTS.
LOSS OF CDKN2A GENE IS A POOR PROGNOSTIC MARKER IN ADULT BCR-ABL1 POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) PATIENTS
IACOBUCCI, ILARIA;Ferrari A;PAPAYANNIDIS, CRISTINA;LONETTI, ANNALISA;TRINO, STEFANIA;ABBENANTE, MARIACHIARA;CATTINA, FEDERICA;PAOLINI, STEFANIA;SOVERINI, SIMONA;Parisi S;MARTINELLI, GIOVANNI
2011
Abstract
Loss of CDKN2A, encoding p16/INK4A and p14/ARF tumor suppressors, has been associated with poorer survival and higher leukemia-initiating- cell-frequency in xenograft models (Notta F et al. Nature 2011). Recently, using genome-wide single nucleotide polymorphisms arrays and gene candidate deep exon sequencing, we identified CDKN2A deletions in 29% (29/101) adult newly diagnosed Ph+ ALL patients and in 47% relapsed cases. Accordingly, here we aimed to investigate the functional consequences of genomic deletions and their prognostic value. By quantitative real-time PCR a significant difference in the expression of CDKN2A was observed among cases with heterozygous (p = 0.04) and homozygous (p = 0.01) loss compared to normal cases, suggesting that deletions lead to CDKN2A haploinsufficiency. In order to investigate their clinical implications, data were collected from 81 patients (median follow-up: 25.2 months- range 2.1-148.1; median age at diagnosis: 54 years- range, 18-76; CDKN2A loss in 29, 36%, cases). 72 patients (89%) were enrolled in the GIMEMA clinical trials (12 patients in GIMEMA LAL0201-B protocol, 13 in LAL2000 and 47 in LAL1205 protocols), while 9 patients (11%) were enrolled into institutional protocols. By univariate analysis a shorter overall survival (OS) and disease-free survival (DFS) were found in patients with CDKN2A deletion compared with those wild-type (OS: 27.7 v 38.2 months, respectively, p = 0.0206; DFS: 10.1 vs 56.1 months, respectively, p = 0.0010). Moreover, a higher cumulative incidence of relapse for patients with CDKN2A deletion (73.3 vs 38.1; p = 0.0014) was also recognized. The multivariate analysis confirmed the negative prognostic impact of CDKN2A deletion on DFS (p = 0051). These results show that there are genetically distinct Ph+ ALL patients with a different risk of leukemia relapse and that testing for CDKN2A alterations at diagnosis may help in risk stratification. Furthermore, since the loss of CDKN2A eliminates the critical tumor surveillance mechanism and allows proliferation, cell growth and tumor formation by the action of MDM2 and CDK4/6, attractive drugs to prevent disease recurrence could be represented by the inhibitors of MDM2 and CDK4/ CDK6. These drugs are currently under investigation in in vitro studies by our group. Supported by: ELN, AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2008, Ateneo RFO grants, Project of integreted program, Programma di Ricerca Regione – Università 2007 – 2009.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
