9 research outputs found
A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy. Although novel emerging drugs are available, the overall prognosis remains poor and new therapeutic approaches are required. PP2A phosphatase is a key regulator of cell homeostasis and is recurrently inactivated in AML. The anticancer activity of several PP2A-activating drugs (e.g., FTY720) depends on their interaction with the SET oncoprotein, an endogenous PP2A inhibitor that is overexpressed in 30% of AML cases. Elucidation of SET regulatory mechanisms may therefore provide novel targeted therapies for SET-overexpressing AMLs. Here, we show that upregulation of protein kinase p38 beta is a common event in AML. We provide evidence that p38 beta potentiates SET-mediated PP2A inactivation by two mechanisms: facilitating SET cytoplasmic translocation through CK2 phosphorylation, and directly binding to and stabilizing the SET protein. We demonstrate the importance of this new regulatory mechanism in primary AML cells from patients and in zebrafish xenograft models. Accordingly, combination of the CK2 inhibitor CX-4945, which retains SET in the nucleus, and FTY720, which disrupts the SET-PP2A binding in the cytoplasm, significantly reduces the viability and migration of AML cells. In conclusion, we show that the p38 beta/CK2/SET axis represents a new potential therapeutic pathway in AML patients with SET-dependent PP2A inactivation
NUP98 is fused to HOXA9 in a variant complex t(7;11;13;17) in a patient with AML-M2
The t(7;11)(p15;p15.4) has been reported to fuse the NUP98 gene (11p15), a component of the nuclear pore complex, with the class-1 homeobox gene HOXA9 at 7p15. This translocation has been associated with myeloid leukemias, predominantly acute myeloid leukemia (AML) M2 subtype with trilineage myelodysplastic features, and with a poor prognosis. The derived fusion protein retains the FG repeat motif of NUP98 N-terminus and the homeodomain shared by the HOX genes, acting as an oncogenic transcription factor critical for leukemogenesis. We report here a new complex t(7;11)-variant, i.e., t(7;11;13;17)(p15;p15;p?;p1?2) in a patient with AML-M2 and poor prognosis. The NUP98-HOXA9 fusion transcript was detected by RT-PCR, suggesting its role in the malignant transformation as it has been postulated for other t(7;11)-associated leukemias. No other fusion transcripts involving the NUP98 or HOXA9 genes were present, although other mechanisms involving several genes on chromosomes 13 and 17 may also be involved. To our knowledge, this is the first t(7;11) variant involving NUP98 described in hematological malignancies
DeterminaciĂłn de enfermedad mĂnima residual molecular en sangre perifĂ©rica mediante NGS como nueva herramienta en el seguimiento posttrasplante alogĂ©nico de progenitores hematopoyĂ©ticos
La determinaciĂłn de la EMR en mĂ©dula Ăłsea y del quimerismo hematopoyĂ©tico (QH) en sangre perifĂ©rica (SP), son herramientas imprescindibles para detectar recaĂdas en el seguimiento
post-alo-TPH. La combinaciĂłn de tecnologĂas mĂĄs sensibles, que identifiquen cambios en el QH, y mĂĄs especĂficos que detecten recaĂdas en
sangre periférica, pueden complementar los estudios de EMR realizados
en mĂ©dula Ăłsea (MO) y permitir tomar decisiones clĂnicas mĂĄs precoces
y especĂficas. El objetivo de este estudio fue valorar la aplicabilidad clĂnica de determinar la EMR molecular mediante Next Generation Sequencing (NGS) en SP en aquellos momentos en los que se observa un cambio del
QH
Assessment of minimal residual disease by next generation sequencing in peripheral blood as a complementary tool for personalized transplant monitoring in myeloid neoplasms
Patients with myeloid neoplasms who relapsed after allogenic hematopoietic stem cell
transplant (HSCT) have poor prognosis. Monitoring of chimerism and specific molecular markers
as a surrogate measure of relapse is not always helpful; therefore, improved systems to detect
early relapse are needed. We hypothesized that the use of next generation sequencing (NGS)
could be a suitable approach for personalized follow-up post-HSCT. To validate our hypothesis,
we analyzed by NGS, a retrospective set of peripheral blood (PB) DNA samples previously evaluated
by high-sensitive quantitative PCR analysis using insertion/deletion polymorphisms (indel-qPCR)
chimerism engraftment. Post-HCST allelic burdens assessed by NGS and chimerism status showed a
similar time-course pattern. At time of clinical relapse in 8/12 patients, we detected positive NGS-based
minimal residual disease (NGS-MRD). Importantly, in 6/8 patients, we were able to detect NGS-MRD
at time points collected prior to clinical relapse. We also confirmed the disappearance of post-HCST
allelic burden in non-relapsed patients, indicating true clinical specificity. This study highlights the
clinical utility of NGS-based post-HCST monitoring in myeloid neoplasia as a complementary specific
analysis to high-sensitive engraftment testing. Overall, NGS-MRD testing in PB is widely applicable
for the evaluation of patients following HSCT and highly valuable to personalized early treatment
intervention when mixed chimerism is detected
Assessment of minimal residual disease by next generation sequencing in peripheral blood as a complementary tool for personalized transplant monitoring in myeloid neoplasms
Patients with myeloid neoplasms who relapsed after allogenic hematopoietic stem cell
transplant (HSCT) have poor prognosis. Monitoring of chimerism and specific molecular markers
as a surrogate measure of relapse is not always helpful; therefore, improved systems to detect
early relapse are needed. We hypothesized that the use of next generation sequencing (NGS)
could be a suitable approach for personalized follow-up post-HSCT. To validate our hypothesis,
we analyzed by NGS, a retrospective set of peripheral blood (PB) DNA samples previously evaluated
by high-sensitive quantitative PCR analysis using insertion/deletion polymorphisms (indel-qPCR)
chimerism engraftment. Post-HCST allelic burdens assessed by NGS and chimerism status showed a
similar time-course pattern. At time of clinical relapse in 8/12 patients, we detected positive NGS-based
minimal residual disease (NGS-MRD). Importantly, in 6/8 patients, we were able to detect NGS-MRD
at time points collected prior to clinical relapse. We also confirmed the disappearance of post-HCST
allelic burden in non-relapsed patients, indicating true clinical specificity. This study highlights the
clinical utility of NGS-based post-HCST monitoring in myeloid neoplasia as a complementary specific
analysis to high-sensitive engraftment testing. Overall, NGS-MRD testing in PB is widely applicable
for the evaluation of patients following HSCT and highly valuable to personalized early treatment
intervention when mixed chimerism is detected
Molecular profiling of immunoglobulin heavychain gene rearrangements unveils new potential prognostic markers for multiple myeloma patients
Multiple myeloma is a heterogeneous disease whose pathogenesis has not been completely elucidated. Although
B-cell receptors play a crucial role in myeloma pathogenesis, the impact of clonal immunoglobulin heavy-chain
features in the outcome has not been extensively explored. Here we present the characterization of complete heavychain gene rearrangements in 413 myeloma patients treated in Spanish trials, including 113 patients characterized by
next-generation sequencing. Compared to the normal B-cell repertoire, gene selection was biased in myeloma, with
significant overrepresentation of IGHV3, IGHD2 and IGHD3, as well as IGHJ4 gene groups. Hypermutation was high in
our patients (median: 8.8%). Interestingly, regarding patients who are not candidates for transplantation, a high
hypermutation rate (â„7%) and the use of IGHD2 and IGHD3 groups were associated with improved prognostic features
and longer survival rates in the univariate analyses. Multivariate analysis revealed prolonged progression-free survival
rates for patients using IGHD2/IGHD3 groups (HR: 0.552, 95% CI: 0.361â0.845, p = 0.006), as well as prolonged overall
survival rates for patients with hypermutation â„7% (HR: 0.291, 95% CI: 0.137â0.618, p = 0.001). Our results provide new
insights into the molecular characterization of multiple myeloma, highlighting the need to evaluate some of these
clonal rearrangement characteristics as new potential prognostic markers
Molecular profiling of immunoglobulin heavychain gene rearrangements unveils new potential prognostic markers for multiple myeloma patients
Multiple myeloma is a heterogeneous disease whose pathogenesis has not been completely elucidated. Although
B-cell receptors play a crucial role in myeloma pathogenesis, the impact of clonal immunoglobulin heavy-chain
features in the outcome has not been extensively explored. Here we present the characterization of complete heavychain gene rearrangements in 413 myeloma patients treated in Spanish trials, including 113 patients characterized by
next-generation sequencing. Compared to the normal B-cell repertoire, gene selection was biased in myeloma, with
significant overrepresentation of IGHV3, IGHD2 and IGHD3, as well as IGHJ4 gene groups. Hypermutation was high in
our patients (median: 8.8%). Interestingly, regarding patients who are not candidates for transplantation, a high
hypermutation rate (â„7%) and the use of IGHD2 and IGHD3 groups were associated with improved prognostic features
and longer survival rates in the univariate analyses. Multivariate analysis revealed prolonged progression-free survival
rates for patients using IGHD2/IGHD3 groups (HR: 0.552, 95% CI: 0.361â0.845, p = 0.006), as well as prolonged overall
survival rates for patients with hypermutation â„7% (HR: 0.291, 95% CI: 0.137â0.618, p = 0.001). Our results provide new
insights into the molecular characterization of multiple myeloma, highlighting the need to evaluate some of these
clonal rearrangement characteristics as new potential prognostic markers