scholarly journals Cooperative Effect of Haploinsufficient ASXL1 and NF1 in Acute Myeloid Leukemia Transformation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1224-1224
Author(s):  
Peng Zhang ◽  
Shohei Yamamoto ◽  
Shi Chen ◽  
Yuan Zhou ◽  
Mingjiang Xu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Negative Regulator ◽  
Class I ◽  
Class Iii ◽  
Genetic Aberrations ◽  
Myeloid Malignancies ◽  
The Impact ◽  
Acute Myeloid

Abstract Objective: The advent of high-throughput whole genome or exome sequencing has led to the identification of almost all genetic aberrations in acute myeloid leukemia (AML). These genetic aberrations have been classified into at least three classes (class I: activate signal transduction pathways and confer a proliferation advantage; class II: affect transcription factors and impair hematopoietic differentiation; class III: concern with epigenetic regulation. AML development is considered to be a multistep process that requires the collaboration of at least two classes of mutations, the so-called "two-hit model". Additional Sex Combs Like 1 (ASXL1) gene, encoding polycomb protein ASXL1, is mutated/deleted with high frequencies in multiple forms of myeloid malignancies, and its alterations are associated with poor prognosis. Hyperactive RAS signaling is also common in myeloid malignancies, which is caused by mutations in the RAS genes or an inactivation of the neurofibromatosis (NF1) gene. The objective of this project is to determine the cooperative effects of NF1 loss (class I) and ASXL1 loss (class III) on the AML development using a novel mouse model with combined haploinsufficiency of Asxl1 and Nf1. Methods: In the current study, we intercrossed Asxl1+/- mice with Nf1+/- mice and characterized the hematopoietic features of Asxl1+/-;Nf1+/- mice in vivo. A serial analyses were used for hematopoietic analysis, including peripheral blood counts, blood smear, morphology, flow cytometry and histology. In vivo tumor transfer was performed to evaluate the malignant nature of the infiltrated cells in moribund/diseased compound Asxl1+/-;Nf1+/- mice. To define the molecular mechanisms by which haploinsufficient Asxl1 and Nf1 cooperate in promoting AML transformation,western blotting was performed to examine the dysregulated histone modifications and RNA-seq was performed to survey the differentially expressed genes in each genotype of mice. Results: A worse survival rate was seen in Asxl1+/-;Nf1+/- mice as compared to all other three groups of control mice, including WT, Nf1+/-, and Asxl1+/- mice. WT and Nf1+/- mice remain disease free till the end of the observed period of time (17 months), while a proportion of aged Asxl1+/- mice developed MDS-like diseases as characterized by multilineage cytopenias and dysplasia, which is consistent with our previous report (Wang et al. Blood 2014). Interestingly, haploinsufficiency of both Asxl1 and Nf1 results in progressive and lethal AML, as reflected by >20% of blasts in the bone marrow. Asxl1+/-;Nf1+/- mice also exhibited an elevated white blood cell counts with anemia and thrombocytopenia, as well as spleno-hepatomegaly. Infiltration of immatured myeloid cells was promident in the spleens and livers of Asxl1+/-;Nf1+/- mice. Tumor transfer assay revealed that the leukemia was transferable to the sub-lethal irradiated recipients, and the secondary transplanted mice displaying a similar phenotype to the primary AML mouse as early as 7 weeks after the tumor transfer. Furthermore, biochemistry study revealed a reduction of the global levels of H3K27me3 in Asxl1+/- c-Kit+ cells. Heterozygous of Nf1 in Asxl1+/- c-Kit+ cellsfurther diminished globle level of H3K27me3. Interestingly, the mRNA expression of Jarid2, an accessory component of polycomb repressive complex-2 (PRC2), was significantly lower in c-Kit+ cells of Asxl1+/-;Nf1+/- micethan that in c-Kit+ cells of other genotypes of mice. The reduced level of Jarid2 may result in further reduction in recruitment of the PRC2 component to the chromatin, dminishing H3K27me3 level. Conclusion: Mutations of NF1, encoding neurofibromin that functions as a negative regulator of RasGTP, are found co-exist with ASXL1 mutations in patients with myeloid malignancies. Our data indicate that combined haploinsufficiency of ASXL1 and NF1 trigger AML transformation through an additive effects to reduce H3K27me3 levels. Together, our data reinforce the impact of combined genetic abnormalities in class I and class III genes in the progression of myeloid malignancies into AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of CMV reactivation on relapse of acute myeloid leukemia after HCT is dependent on disease stage and ATG

2021 ◽  
Author(s):  
Amin T. Turki ◽  
Nikolaos Tsachakis-Mück ◽  
Saskia Leserer ◽  
Pietro Crivello ◽  
Tobias Liebregts ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Advanced Disease ◽  
Survival Rates ◽  
Disease Stage ◽  
The Impact ◽  
Cmv Reactivation ◽  
Acute Myeloid

Cytomegalovirus (CMV) reactivation is a frequent complication after allogeneic hematopoietic cell transplantation (HCT), whose impact on clinical outcome, in particular on leukemic relapse is controversial. We retrospectively analyzed 687 HCT recipients with acute myeloid leukemia (AML) and ciclosporin-based immunosuppression to better understand the differential impact of CMV on transplant outcomes depending on AML disease stage and in-vivo T-cell depletion with anti-thymocyte globulin (ATG). Without ATG, CMV reactivation associated with significantly reduced relapse, yet its effect was more pronounced for advanced disease AML (p=0.0002) than for patients in first complete remission (CR1, p=0.0169). Depending on the disease stage, ATG exposure abrogated relapse protection following CMV reactivation in advanced stages (p=0.796), while it inverted its effect into increased relapse for CR1 patients (p=0.0428). CMV reactivation was associated with significantly increased non-relapse mortality in CR1 patients without ATG (p=0.0187), but not in those with advanced disease and ATG. Following CMV reactivation, only patients with advanced disease had significantly higher event-free survival rates as compared to patients without CMV. Overall, our data suggest that both ATG and disease stage modulate the impact of post-HCT CMV reactivation in opposite directions, revealing a level of complexity that warrants future studies regarding the interplay between anti-virus and anti-tumor immunity.

Degradation of TRAF6 by Bortezomib-Induced Autophagy Contributes to Cell Death in Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2452-2452
Author(s):  
Jing Fang ◽  
Lyndsey Bolanos ◽  
Garrett Rhyasen ◽  
Carmen Rigolino ◽  
Agostino Cortelezzi ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
26S Proteasome ◽  
Negative Regulator ◽  
Myeloid Malignancies ◽  
Chromosome 5Q ◽  
Acute Myeloid

Abstract Abstract 2452 Deletion of chromosome 5q in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients results in loss of miR-146a, which is a negative regulator of the innate immune pathway by targeting TNF receptor associated factor-6 (TRAF6). Therefore, MDS and AML patients with reduced miR-146a expression concomitantly exhibit elevated TRAF6 protein. TRAF6 is an E3 ubiquitin ligase that catalyzes K63-linked polyubiquitin chains on substrates that lead to pathway activation, one of which includes NF-kB. Mice lacking miR-146a, or with overexpression of TRAF6, develop AML- and MDS-like features. Bortezomib (Velcade©), which shows promise alone or in combination with chemotherapy in certain groups of MDS and AML patients, is a selective and reversible inhibitor of the 26S proteasome. Studies on the mechanism of action of Bortezomib have shown that pro-apoptotic proteins are stabilized following proteasome inhibition and contribute to the anti-cancer effect. In this report, paradoxically, we find that Bortezomib induces rapid and complete degradation of TRAF6 protein, but not mRNA, in MDS/AML cell lines and human CD34+ cells. A similar finding was observed when AML cells were treated with MG132, another proteasome inhibitor, indicating that degradation of TRAF6 is secondary to proteasomal inhibition. Interestingly, the reduction in TRAF6 protein coincides with Bortezomib-induced autophagy, as indicated by conversion of LC3B-I to LC3B-II and degradation of SQSTM1/p62, and subsequently with apoptosis in MDS/AML cells. Addition of an autophagy inhibitor (3-methyladenine [3-MA]) to Bortezomib-treated AML cells maintained TRAF6 protein expression and enhanced cell viability. Similarly, TRAF6 degradation was blocked by 3-MA when cells were treated with Rapamycin, an mTOR inhibitor and inducer of autophagy. These findings suggest that a mechanism of Bortezomib-induced cell death in myeloid malignancies involves elimination of TRAF6 protein by autophagosomes. Forced expression of TRAF6 in two AML cell lines partially blocked the cytotoxic effect of Bortezomib, suggesting that TRAF6 is an important target of Bortezomib. To determine whether loss of TRAF6 is sufficient to impede growth of MDS and AML, we used a genetic approach to inhibit TRAF6 in MDS/AML cell lines and bone marrow cells from MDS patients with deletion of chromosome 5q. RNAi-mediated depletion of TRAF6 in MDS and AML samples resulted in impaired malignant hematopoietic stem/progenitor function and rapid apoptosis. To uncover the molecular consequences following loss of TRAF6, we applied gene expression profiling and identified genes relevant to the survival of MDS and AML cells. In summary, these findings implicate TRAF6 in Bortezomib-induced cell death and in the maintenance of myeloid malignancies, and reveal a novel mechanism of TRAF6 regulation through autophagic degradation. Disclosures: Oliva: Celgene: Consultancy.

scholarly journals SMPDL3B Predicts Poor Prognosis and Contributes to Development of Acute Myeloid Leukemia

2021 ◽  
Vol 8 ◽  
Author(s):  
Huiqing Qu ◽  
Ye Zhu
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Human Cancer ◽  
Negative Regulator ◽  
Poor Overall Survival ◽  
Clinicopathologic Characteristics ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML), characterized by the low cure rate and high relapse, urgently needs novel diagnostic or prognostic biomarkers and potential therapeutic targets. Sphingomyelin Phosphodiesterase Acid Like 3B (SMPDL3B) is a negative regulator of Toll-like receptor signaling that plays important roles in the interface of membrane biology and innate immunity. However, the potential role of SMPDL3B in human cancer, especially in AML, is still unknown.Methods: The expression of SMPDL3B in AML samples was investigated through data collected from Gene Expression Omnibus (GEO). Association between SMPDL3B expression and clinicopathologic characteristics was analyzed with the chi-square test. Survival curves were calculated by the Kaplan–Meier method. Cox univariate and multivariate analyses were used to detect risk factors for overall survival. The biological functions of SMPDL3B in human AML were investigated both in vitro and in vivo.Results: Expression of SMPDL3B mRNA was significantly upregulated in human AML samples and closely correlated to cytogenetics risk and karyotypes. Elevated expression of SMPDL3B was associated with poor overall survival and emerged as an independent predictor for poor overall survival in human AML. Blocked SMPDL3B expression inhibited AML cells growth both in vitro and in vivo via promoting cell apoptosis.Conclusion: Taken together, our results demonstrate that SMPDL3B could be used as an efficient prognostic biomarker and represent a potential therapeutic target for human AML.

Inhibition of Histone Deacetylases 1 and 6 Enhances Ara-C-Induced Apoptosis In Pediatric Acute Myeloid Leukemia Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3275-3275
Author(s):  
Xuelian Xu ◽  
Chengzhi Xie ◽  
Holly Edwards ◽  
Hui Zhou ◽  
Steven Buck ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Class I ◽  
Pediatric Aml ◽  
Induced Apoptosis ◽  
Class I Hdacs ◽  
The Impact ◽  
Acute Myeloid

Abstract Abstract 3275 Acute myeloid leukemia (AML) accounts for one-fourth of acute leukemias in children, but is responsible for more than half of the leukemia deaths in this patient population. Resistance to cytarabine (ara-C)-based chemotherapy is a major cause of treatment failure in this disease. Therefore, new therapies for children with AML are urgently needed. Among the newer agents that have been recently investigated in high-risk AML in adults, histone deacetylase (HDAC) inhibitors [HDACIs, e.g., valproic acid (VPA) and Vorinostat (SAHA)] are particularly notable. The ability of HDACIs to induce cell differentiation, cell cycle arrest, and apoptosis in human leukemic cells, but not in normal cells, has stimulated significant interest in their potential as anti-leukemia agents. Numerous HDACIs have been developed during the last decade and the majority of these are in clinical trials including the novel class I-selective HDACIs, MS-275 and MGCD0103, and pan-HDACIs, LBH-589 and PXD101. Despite the well-characterized molecular and cellular effects of HDACIs, single-agent activity for this class of drugs has been modest. However, the clinical usefulness of HDACIs may be increased through rationally designed combination strategies including HDACIs with standard chemotherapy drugs. We previously hypothesized that VPA synergizes with ara-C, resulting in enhanced antileukemic activity in pediatric AML, by inducing apoptosis. We examined the impact of VPA on ara-C cytotoxicities in a panel of pediatric AML cell lines and diagnostic blast samples from children with de novo AML and demonstrated highly synergistic antileukemic activities of combined ara-C and VPA. This was especially pronounced in samples with t(8;21). Our mechanistic studies revealed that induction of DNA damage and Bim underlay the synergistic antileukemic activities of this drug combination. The present study was designed to identify members of the HDAC family which were deteminants of ara-C sensitivities, and to select the optimal HDACIs that were most efficacious when combined with ara-C for treating AML. Expression profiles of HDACs 1–11 in 4 clinically relevant pediatric AML cell lines (THP-1, Kasumi-1, MV4-11, and CMS) suggested that HDACs 5 and 11 were likely not involved due to marginal or lack of expression. The remaining class II HDACs and the entire class I enzymes could be relevant to HDACI anti-leukemic activities, based on the relationships between HDAC levels and HDACI cytotoxicities and responses to the combined VPA and ara-C, although the impact of class I HDACs seemed to predominate. Treatment of THP-1 cells with structurally-diverse HDACIs [SAHA (a pan-HDACI), VPA (a relatively class I selective-HDACI), and MS-275 (a class I selective-HDACI)] and enzymatic assays following immunoprecipitation of class I HDACs, revealed that inhibition of class I HDACs could augment ara-C-induced apoptosis. However, class II HDACs (e.g., HDAC6) were also implicated since SAHA was also effective. shRNA knockdown of HDACs 1 or 6 resulted in ∼2-fold increased apoptosis induced by ara-C in THP-1 AML cells (p<0.05). This was accompanied by substantially increased expression of Bim (2.3- and 1.4-fold, respectively). Down-regulation of HDAC2 resulted in ∼30% decreased ara-C-induced apoptosis. In contrast, shRNA knockdown of HDACs 3 and 4 had no effects on ara-C-induced apoptosis in THP-1 cells. At clinically achievable concentrations, HDACIs that simultaneously inhibited both HDACs 1 and 6 showed the best anti-leukemic activities and significantly enhanced ara-C-induced apoptosis in pediatric AML sublines including THP-1 and Kasumi-1. Our results further establish that HDACs are promising therapeutic targets for treating pediatric AML and identified HDACs 1 and 6 as the most relevant drug targets. Accordingly, treating pediatric AML patients with pan-HDACIs may be more beneficial than HDAC isoform-specific drugs. Based on our results, incorporation of pan-HDACIs (e.g., LBH-589 and PXD101) into ara-C-based clinical trials for treating pediatric AML should be strongly considered. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The pan-class I phosphatidyl-inositol-3 kinase inhibitor NVP-BKM120 demonstrates anti-leukemic activity in acute myeloid leukemia

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Matteo Allegretti ◽  
Maria Rosaria Ricciardi ◽  
Roberto Licchetta ◽  
Simone Mirabilii ◽  
Stefania Orecchioni ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Phosphatidyl Inositol ◽  
Class I ◽  
Clinical Activity ◽  
Dependent Manner ◽  
Acute Myeloid

Abstract Aberrant activation of the PI3K/Akt/mTOR pathway is a common feature of acute myeloid leukemia (AML) patients contributing to chemoresistance, disease progression and unfavourable outcome. Therefore, inhibition of this pathway may represent a potential therapeutic approach in AML. The aim of this study was to evaluate the pre-clinical activity of NVP-BKM120 (BKM120), a selective pan-class I PI3K inhibitor, on AML cell lines and primary samples. Our results demonstrate that BKM120 abrogates the activity of the PI3K/Akt/mTOR signaling, promoting cell growth arrest and significant apoptosis in a dose- and time-dependent manner in AML cells but not in the normal counterpart. BKM120-induced cytotoxicity is associated with a profound modulation of metabolic behaviour in both cell lines and primary samples. In addition, BKM120 synergizes with the glycolitic inhibitor dichloroacetate enhancing apoptosis induction at lower doses. Finally, in vivo administration of BKM120 to a xenotransplant mouse model of AML significantly inhibited leukemia progression and improved the overall survival of treated mice. Taken together, our findings indicate that BKM120, alone or in combination with other drugs, has a significant anti-leukemic activity supporting its clinical development as a novel therapeutic agent in AML.

scholarly journals Lineage tracing of acute myeloid leukemia reveals the impact of hypomethylating agents on chemoresistance selection

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Francisco Caiado ◽  
Diogo Maia-Silva ◽  
Carolina Jardim ◽  
Nina Schmolka ◽  
Tânia Carvalho ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Dna Methyltransferase ◽  
Cancer Recurrence ◽  
Lineage Tracing ◽  
Leukemic Cells ◽  
The Impact ◽  
Acute Myeloid

Abstract Chemotherapy-resistant cancer recurrence is a major cause of mortality. In acute myeloid leukemia (AML), chemorefractory relapses result from the complex interplay between altered genetic, epigenetic and transcriptional states in leukemic cells. Here, we develop an experimental model system using in vitro lineage tracing coupled with exome, transcriptome and in vivo functional readouts to assess the AML population dynamics and associated molecular determinants underpinning chemoresistance development. We find that combining standard chemotherapeutic regimens with low doses of DNA methyltransferase inhibitors (DNMTi, hypomethylating drugs) prevents chemoresistant relapses. Mechanistically, DNMTi suppresses the outgrowth of a pre-determined set of chemoresistant AML clones with stemness properties, instead favoring the expansion of rarer and unfit chemosensitive clones. Importantly, we confirm the capacity of DNMTi combination to suppress stemness-dependent chemoresistance development in xenotransplantation models and primary AML patient samples. Together, these results support the potential of DNMTi combination treatment to circumvent the development of chemorefractory AML relapses.

scholarly journals Occupational pesticide exposure increases risk of acute myeloid leukemia: a meta-analysis of case–control studies including 3,955 cases and 9,948 controls

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Amelie Foucault ◽  
Nicolas Vallet ◽  
Noemie Ravalet ◽  
Frederic Picou ◽  
Marie C. Bene ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Pesticide Exposure ◽  
Meta Analysis ◽  
Case Control ◽  
Health Concern ◽  
Case Control Studies ◽  
Myeloid Malignancies ◽  
The Impact ◽  
Acute Myeloid

AbstractThe impact of pesticides on health is a major public health concern. A higher risk to develop chronic lymphoid malignancies has been demonstrated to be associated with occupational pesticide exposure (OPE). By contrast, little is known of the impact of OPE on the occurrence of myeloid malignancies especially acute myeloid leukemia (AML). The purpose of this meta-analysis is to summarize data on the association between OPE and AML. A relevant dataset of case–control studies was extracted. Among 6784 references extracted, 14 were selected, representing 3,955 AML patients and 9,948 control subjects diagnosed between 1976 and 2010. An adverse association was found between OPE and AML (OR = 1.51; 95%CI: 1.10–2.08), not affected by sensitivity analyses. Funnel plot asymmetry suggested a publication bias underestimating OR. Stratified analysis showed the association to be driven by studies with: (1) monocentric AML patients and hospital-based control population, (2) Newcastle–Ottawa scale > 6 and the group of studies identified as with the lowest risk, (3) exposure assessment through peer-to-peer interview, (4) diagnosis in North America and Asia and after 1995, (5) restriction to de novo AML. Moreover, the association between OPE and AML was significant with insecticides. These findings broaden the spectrum of pesticide toxicity to myeloid malignancies.

AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations

Blood ◽  
2009 ◽  
Vol 114 (26) ◽  
pp. 5352-5361 ◽  
Author(s):  
Jih-Luh Tang ◽  
Hsin-An Hou ◽  
Chien-Yuan Chen ◽  
Chieh-Yu Liu ◽  
Wen-Chien Chou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Remission Rate ◽  
Adult Patients ◽  
Poor Prognostic Factor ◽  
The Impact ◽  
Runx1 Mutation ◽  
Acute Myeloid

AbstractSomatic mutation of the AML1/RUNX1(RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and in AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 persons (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male sex, older age, lower lactic dehydrogenase value, French-American-British M0/M1 subtypes, and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19, and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD but negatively associated with CEBPA and NPM1 mutations. AML patients with RUNX1 mutations had a significantly lower complete remission rate and shorter disease-free and overall survival than those without the mutation. Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival. Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidence that RUNX1 mutations are associated with distinct biologic and clinical characteristics and poor prognosis in patients with de novo AML.

scholarly journals Proteomic Studies of Primary Acute Myeloid Leukemia Cells Derived from Patients Before and during Disease-Stabilizing Treatment Based on All-Trans Retinoic Acid and Valproic Acid

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2143
Author(s):  
Maria Hernandez-Valladares ◽  
Rebecca Wangen ◽  
Elise Aasebø ◽  
Håkon Reikvam ◽  
Frode S. Berven ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Acute Myeloid Leukemia ◽  
Retinoic Acid ◽  
Protein Kinase ◽  
Myeloid Leukemia ◽  
Rna Metabolism ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Acute Myeloid

All-trans retinoic acid (ATRA) and valproic acid (VP) have been tried in the treatment of non-promyelocytic variants of acute myeloid leukemia (AML). Non-randomized studies suggest that the two drugs can stabilize AML and improve normal peripheral blood cell counts. In this context, we used a proteomic/phosphoproteomic strategy to investigate the in vivo effects of ATRA/VP on human AML cells. Before starting the combined treatment, AML responders showed increased levels of several proteins, especially those involved in neutrophil degranulation/differentiation, M phase regulation and the interconversion of nucleotide di- and triphosphates (i.e., DNA synthesis and binding). Several among the differentially regulated phosphorylation sites reflected differences in the regulation of RNA metabolism and apoptotic events at the same time point. These effects were mainly caused by increased cyclin dependent kinase 1 and 2 (CDK1/2), LIM domain kinase 1 and 2 (LIMK1/2), mitogen-activated protein kinase 7 (MAPK7) and protein kinase C delta (PRKCD) activity in responder cells. An extensive effect of in vivo treatment with ATRA/VP was the altered level and phosphorylation of proteins involved in the regulation of transcription/translation/RNA metabolism, especially in non-responders, but the regulation of cell metabolism, immune system and cytoskeletal functions were also affected. Our analysis of serial samples during the first week of treatment suggest that proteomic and phosphoproteomic profiling can be used for the early identification of responders to ATRA/VP-based treatment.

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