NPM1 Mutated AML Is Associated With Lower Expression Of Poor Prognostic Markers BAALC, ERG and MN1 In Adult Patients With Acute Myeloid Leukaemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4945-4945 ◽  
Author(s):  
Poonkuzhali Balasubramanian ◽  
Ashok kumar Jayavelu ◽  
Ajay Abraham ◽  
Savitha Varatharajan ◽  
Sreeja Karathedath ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Markers ◽  
Normal Karyotype ◽  
Adult Patients ◽  
Rna Expression ◽  
Flt3 Mutations ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a clinically and biologically complex and heterogeneous hematopoietic neoplasm. Recent advances in acute myeloid leukemia (AML) biology have lead to prognosticate and predict treatment outcome in AML based on molecular markers. Mutations in NPM1, CEBPA are considered good prognosis and High BAALC, ERG & MN1 expression associate with worse outcome in AML patients treated with standard chemotherapy. Although many efforts have been made to identify genetic mutations and modulated gene expression levels that can be used to predict outcomes in patients with AML, the association between these prognostic markers has not been evaluated. We have reported previously that the NPM1 mutated patients have significantly high dCK and hENT1 gene expression (involved in cytarabine metabolism) and low ABCG2 and ABCB1transporter expression (Abraham et al, ASH abstracts; Nov 2011; 118: 3481 and Nov 2012; 120: 143), suggesting that the good prognostic nature of this mutation is possibly due to the better metabolism and transport of the chemotherapeutic drugs used in induction therapy.  We extended this study to look for association between NPM1/FLT3 mutation status and the RNA expression of other good or poor prognostic markers in patients with AML. We prospectively included 274 adult patients with AML in this study. The median age was 42 years (range 16-74y). AML was diagnosed according to the FAB and WHO classifications. There were 238 patients with de novo AML; Secondary AML -6; Therapy related AML- 2 and Relapsed AML-28. Bone marrow cytogenetics and immunophenotyping analysis was available for all patients at diagnosis and/or relapse. Diagnostic bone marrow MNCs were isolated by ficoll- density gradient centrifugation and stored in trizol reagent for RNA expression and mutation detection. RT-PCR was used to screen AML-ETO and Inv 16, and the expression of BAALC, ERG1, MN1, CXCR4 and WT1were analyzed using RQ-PCR. NPM1-c, FLT3 ITD and TKD were screened using DNA PCR followed by gene-scan, sequencing or RFLP methods. The basic demographics and the frequency of the markers are listed in Table 1. When analyzed separately in normal karyotype AML (NK-AML), the frequencies of the mutations were: NPM1: 52.2%; FLT3-ITD: 24%; TKD: 4.3%. When the RNA expression of BAALC, WT1, ERG1, CXCR4 and MN1 was compared in patients with NPM1 or FLT3 mutations, we noticed that patients with NPM1 had significantly low expression of BAALC, MN1 and ERG1 while those with FLT3 mutations (ITD or TKD) had higher expression of these genes (Figure1). There was no significant association with CXCR4 or WT1 expression and these mutations. When analyzed separately in the normal karyotype AML, these associations were still significant. In addition, the relapsed patients had significantly higher expression of BAALC, MN1, and ERG1 RNA compared to de-novoAML cases (data not shown). To conclude, we show that NPM1 or FLT3 mutations acquire the prognostic significance due to several factors including BAALC, ERG1 and MN1expression levels in addition to drug metabolizing enzymes’ and drug transporter expression. These factors must be taken into consideration when attempting to personalize chemotherapy in AML. Disclosures: No relevant conflicts of interest to declare.

Activating FLT3 Mutations Display a Wide Range Of Transforming Potential and a Characteristic Pathway Profile Associated With Prognosis In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1312-1312
Author(s):  
Hanna Janke ◽  
Friederike Schneider ◽  
Daniela Schumacher ◽  
Tobias Herold ◽  
Hopfner Karl-Peter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Gene Expression Profile ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Wide Range ◽  
Flt3 Mutations ◽  
Acute Myeloid

Abstract Background Internal tandem duplication (ITD) and pointmutations in the tyrosine kinase domain (TKD) of the receptor tyrosine kinase FLT3 occur in about 30% of patients with acute myeloid leukemia (AML). In contrast to the negative prognostic impact of FLT3-ITD in normal karyotype AML, FLT3 pointmutations occurring in the TKD and juxtamembrane (JM) region are less frequent and of unclear clinical impact. Although TKD mutations can induce resistance to tyrosine kinase inhibitors the individual transforming potential of FLT3 pointmutations has not been analysed in detail. In this study we have performed a comprehensive analysis of various FLT3 mutants in a comparative setting in vitro and analyzed gene expression profiles, and clinical outcome with respect to FLT3mutation status. Material and Methods We analyzed relapse and survival in 672 cytogenetically normal AML patients and the FLT3 status at diagnosis and relapse in 156 patients. In the murine Ba/F3 cell model we analyzed the transforming potential, subcellular localization, phosphorylation status and signaling properties of eight different FLT3 mutants. The investigated FLT3 mutations include three ITD of different length and insertion site, V592A in the JM region, common FLT3-TKD mutations D835V and D835Y as well as D839G and I867S in the second TKD. FLT3-D839G and -I867S were recently found in AML patients by our group during routine diagnostics but have not been functionally characterized before. The corresponding remission samples did not express these mutations. Further a gene expression profile analysis with respect to FLT3-ITD and -TKD mutation status and evaluation of differences in activation of predefined STAT5 target gene set was performed. Results In 672 normal karyotype AML patients FLT3-ITD, but not FLT3-TKD mutations were associated with an inferior relapse free and overall survival in multivariate analysis. In paired diagnosis-relapse samples FLT3-ITD showed higher stability (70%) compared to FLT3-TKD (30%). In vitro, FLT3-ITD induced a fully transformed phenotype in Ba/F3 cells, whereas FLT3 pointmutations showed a weaker but clearly transformed phenotype with gradual increase in proliferation and protection from apoptosis. The transforming capacity of the investigated mutants was associated with cell surface expression and tyrosine 591 phosphorylation of the FLT3 receptor. Western blot experiments revealed STAT5 activation only in FLT3-ITD transformed cells, further gene expression profile analyses displayed differences in predefined STAT5 target genes between FLT3-ITD and FLT3-TKD mutations. In contrast, FLT3-non-ITD mutants had an enhanced signal of AKT and MAPK activation. Further differences were found on mRNA level presenting deregulation of SOCS2, ENPP2, PRUNE2 and ART3 expression between FLT3-ITD, FLT3-TKD and FLT3-WT. Conclusion Although apparently divergent in response to treatment all functionally characterized mutants showed a clear gain-of-function phenotype with a wide range of transforming activity associated with clinical prognosis and signaling. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Mutation detection in thousands of acute myeloid leukemia cells using single cell RNA-sequencing

2018 ◽  
Author(s):  
Allegra A. Petti ◽  
Stephen R. Williams ◽  
Christopher A. Miller ◽  
Ian T. Fiddes ◽  
Sridhar N. Srivatsan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Single Cell ◽  
Rna Sequencing ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Integrative Approach ◽  
Single Cell Rna Sequencing ◽  
Acute Myeloid

AbstractVirtually all tumors are genetically heterogeneous, containing subclonal populations of cells that are defined by distinct mutations1. Subclones can have unique phenotypes that influence disease progression2, but these phenotypes are difficult to characterize: subclones usually cannot be physically purified, and bulk gene expression measurements obscure interclonal differences. Single-cell RNA-sequencing has revealed transcriptional heterogeneity within a variety of tumor types, but it is unclear how this expression heterogeneity relates to subclonal genetic events – for example, whether particular expression clusters correspond to mutationally defined subclones3,4,5,6-9. To address this question, we developed an approach that integrates enhanced whole genome sequencing (eWGS) with the 10x Genomics Chromium Single Cell 5’ Gene Expression workflow (scRNA-seq) to directly link expressed mutations with transcriptional profiles at single cell resolution. Using bone marrow samples from five cases of primary human Acute Myeloid Leukemia (AML), we generated WGS and scRNA-seq data for each case. Duplicate single cell libraries representing a median of 20,474 cells per case were generated from the bone marrow of each patient. Although the libraries were 5’ biased, we detected expressed mutations in cDNAs at distances up to 10 kbp from the 5’ ends of well-expressed genes, allowing us to identify hundreds to thousands of cells with AML-specific somatic mutations in every case. This data made it possible to distinguish AML cells (including normal-karyotype AML cells) from surrounding normal cells, to study tumor differentiation and intratumoral expression heterogeneity, to identify expression signatures associated with subclonal mutations, and to find cell surface markers that could be used to purify subclones for further study. The data also revealed transcriptional heterogeneity that occurred independently of subclonal mutations, suggesting that additional factors drive epigenetic heterogeneity. This integrative approach for connecting genotype to phenotype in AML cells is broadly applicable for analysis of any sample that is phenotypically and genetically heterogeneous.

Diverse Roles of Hepatocyte Growth Factor (HGF) in Normal Karyotype Acute Myeloid Leukemia (AML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3107-3107
Author(s):  
Ian McInnis ◽  
Theresa Hahn ◽  
Anasitasia Ioane ◽  
Ashleigh Lamson ◽  
Deepika Lal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Growth Factor ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Normal Bone Marrow ◽  
Normal Bone ◽  
Hepatocyte Growth ◽  
Acute Myeloid

Abstract Abstract 3107 Poster Board III-44 Prior studies have demonstrated that hepatocyte growth factor (HGF) regulates proliferation and differentiation of normal hematopoietic progenitors. HGF activity occurs primarily via interactions with the c-met receptor, a tyrosine kinase receptor found on epithelial and some cancer cells. In solid tumors, HGF/c-met interactions mediate increased neoplastic invasion, metastases, and angiogenesis. However, in vitro, HGF has also been shown to mediate anti-tumor effects in leukemia cell line models. To better elucidate the role of HGF in acute leukemogenesis, we evaluated HGF and c-met gene expression in 91 normal karyotype acute myeloid leukemia (NK-AML) patient samples previously characterized for marrow angiogenesis (CD31+ microvessels), FLT-3/NPM-1 gene mutation, and pro-angiogenic factors and receptors (specifically vascular endothelial growth factors (VEGF-A and C) and their receptors). Median patient age was 66 years (range 21-87) with 49 women and 42 men. AML disease FAB subtypes M2 (37%) and M1 (36%) subtypes were most common. Median presenting white blood cell count (WBC) was 32,000/μL (range 0.43-555,000/μL) with marrow blasts of 70.6% (range 15-95.4%). Fourteen percent presented with extramedullary disease. Median OS was 9.4 months (95% CI 6.7 to 11.5 months), with median EFS of 8 months (95% CI 5.7 to 11.5 months) for all patients. Seventy-nine patients received cytarabine and anthracycline-based induction chemotherapy with 58% (n=46) achieving complete remission (CR). Marrow aspirate samples were evaluated by quantitative real-time polymerase chain reaction with levels expressed relative to normal bone marrow controls (set =1). We found that HGF gene expression was upregulated in most primary NK-AML patient samples, with 88% expressing higher HGF than normal bone marrow. Median HGF expression in AML samples was 7.73 fold higher than normal controls. Multivariate analysis including age, complete remission, marrow blasts, extramedullary disease, and expression of other angiogenic factors and receptors as covariables, showed high HGF expression to be significantly associated with both longer overall and event-free survival. Surprisingly, HGF gene expression was found to be negatively correlated with microvessel density and NPM-1 mutation and positively correlated with the VEGF receptor neuropilin-1 (NRP-1) which has been reported to function as co-mediator of HGF activity. No association between HGF and FLT-3 ITD mutation was noted. The majority of AML samples did not express the HGF receptor, c-met, suggesting that HGF function in AML occurs primarily via paracrine interactions with surrounding vascular and stromal cells and/or HGF/NRP-1 autocrine pathways. Further analysis confirmed no significant correlation between HGF and c-met gene expression in AML samples but did demonstrate a subset of NPM-1+ HGF+ AML samples (n=7) expressing high levels of both HGF and c-met (p=0.0005, r=0.96). To confirm whether HGF/c-met autocrine interactions contributed to leukemogenesis in these cells, we treated immunodeficient mice engrafted with an HGF+ c-met+ human AML cell line (HEL) with vehicle vs. a c-met tyrosine kinase inhibitor, and noted growth inhibitory effects following c-met blockade. Conclusions HGF gene expression was an independent predictive factor for improved clinical outcome and was associated with NRP-1 expression, lower microvessel density, and NPM-1 negative status in normal karyotype AML patients. A subset of AML samples was identified with high concordant HGF and c-met expression consistent with autocrine pathways. Inhibition of HGF/c-met interactions in a preclinical AML model exerted anti-tumor effects. Additional studies of the diverse roles of HGF in myeloid leukemogenesis are warranted. Disclosures No relevant conflicts of interest to declare.

FLT3 mutations have no prognostic impact in elderly patients with acute myeloid leukemia and normal karyotype

2009 ◽  
Vol 84 (8) ◽  
pp. 532-534 ◽  
Author(s):  
Felicetto Ferrara ◽  
Clelia Criscuolo ◽  
Cira Riccardi ◽  
Tiziana Izzo ◽  
Mariangela Pedata ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Flt3 Mutations ◽  
Acute Myeloid

scholarly journals BCOR Mutations in Acute Myeloid Leukemia: Clonal Evolution and Prognosis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-4
Author(s):  
Ashley Zhang ◽  
Yuntao Liu ◽  
Shuning Wei ◽  
Benfa Gong ◽  
Chunlin Zhou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Statistical Difference ◽  
Tp53 Mutation ◽  
Clonal Evolution ◽  
Normal Karyotype ◽  
Abnormal Karyotype ◽  
Acute Myeloid

Background BCOR gene is a transcription repressor that may influence normal hematopoiesis and is associated with poor prognosis in acute myeloid leukemia (AML) with normal karyotype. However, due to the rare mutation frequency in AML (3.8%-5%), clinical characteristics and prognosis of AML patients with BCOR mutation including abnormal karyotype are still unknown. In addition, the clonal evolution of AML patients with BCOR mutation has not been fully investigated. Methods By means of next generation of sequencing, we performed sequencing of 114 genes related to hematological diseases including BCOR on 509 newly diagnosed AML patients (except for acute promyelocytic leukemia) from March 2017 to April 2019. The 2017 European Leukemia Net (ELN) genetic risk stratification was used to evaluate prognosis. Overall survival (OS) was defined as the time from diagnosis to death or last follow-up. Relapse-free survival (RFS) was measured from remission to relapse or death. Clonal evolution was investigated through analyzing bone marrow samples at diagnosis, complete remission (CR) and relapse from the same patient. Result Among 509 AML patients, we found BCOR mutations in 23 patients (4.5%). BCOR mutations were enriched in patients with mutations of RUNX1 (p = 0.008) and BCORL1 (p = 0.0003). Patients with BCOR mutation were more at adverse ELN risk category compared to patients without BCOR mutation (p = 0.007). Besides, there was a larger proportion of patients with normal karyotype in BCOR mutation group but it had not reached statistical difference (62.5% vs 45.5%, p = 0.064). The abnormal karyotype in patients with BCOR mutations included trisomy 8, t(9;11), inv(3), -7 and complex karyotype.There were no significant differences in age, sex, white blood cell count, hemoglobin or platelet count between the two groups. More patients died during induction (13.0% vs 3.5%, p = 0.56) and fewer patients achieved CR after 2 cycles of chemotherapy when patients had BCOR mutations (69.6% vs 82.5%, p = 0.115) but the difference had not reached statistical difference . Patients with BCOR mutations had inferior 2-year OS (52.1% vs 70.7%, p = 0.0094) and 2-year RFS (29.8% vs 61.1%, p = 0.0090). After adjustment for ELN risk stratification, BCOR mutation was still remain a poor prognostic factor. However, the adverse prognostic impact of BCOR mutation is overcome by hematopoietic stem cell transplantation (HSCT), in which there was no difference between BCOR mutation group and wild type group (p = 0.474) (Figure 1). Through analysis of paired bone marrow sample at diagnosis, remission and relapse, we revealed the clonal evolution that BCOR mutation was only detected at diagnosis sample as a subclone and diminished at CR and relapse while TP53 mutation was only detected at relapse with a variant allele frequency (VAF) of 25.5%. We also found BCOR mutation at another patient's diagnosis and relapse sample while TP53 mutation was detected at relapse with VAF of 11.8%. Conclusion BCOR is associated with RUNX1 mutation and higher ELN risk. AML patients with BCOR mutation including normal and abnormal karyotype conferred a worse impact on OS that can be overcome by HSCT. BCOR mutation is a subclone at diagnosis or relapse in some patients, in which TP53 mutation clone occurred at relapse. Disclosures No relevant conflicts of interest to declare.

Comparison of Outcomes of Bone Marrow and Umbilical Cord Blood Transplants from Unrelated Donors in Adult Patients with Acute Myeloid Leukemia/Myelodysplastic Syndrome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2010-2010
Author(s):  
Kazuhiro Masuoka ◽  
Shigesaburo Miyakoshi ◽  
Kazuya Ishiwata ◽  
Masanori Tsuji ◽  
Shinsuke Takagi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Cord Blood ◽  
Myeloid Leukemia ◽  
Adult Patients ◽  
Refractory Anemia ◽  
Unrelated Donor ◽  
Graft Versus Host ◽  
Unrelated Donors ◽  
Acute Myeloid

Abstract <Objectives> Promising results of cord blood transplants from unrelated donors have been reported in adults. To compare of outcomes of bone marrow transplants (BMT, n = 51), and umbilical cord blood transplants (UCBT, n = 110) from unrelated donors in adult patients with acute myeloid leukemia (AML) / myelodysplastic syndrome (MDS), we analyzed retrospectively the results of 161 adult patients with AML and MDS in our hospital. <Patients and Methods> We reviewed medical records of 161 patients with AML/MDS who had received a hematopoietic stem cell transplant from an unrelated donor between August 2000 and April 2007 at Toranomon Hospital, Tokyo, Japan. <Results> Patient’s median age was 55 years (17–71). Diagnoses include de novo AML (n =85), MDS overt AML (n=48), refractory anemia (RA) (n=13), and refractory anemia with excess of blasts (RAEB) (n=15). Disease status consisted of standard (CR1 of AML and RA, n=30) and advanced (other status, n=131). Recipients of UCBT had more advanced disease than recipients of BMT at the time of transplantation (89 percent vs. 65 percent, P<0.001). The median number of nucleated cells that were infused was 0.26×108 per kilogram of the recipient’s body weight for cord blood and 2.5×108 per kilogram for bone marrow (P<0.001). The major difference were higher number in the UCBT group of HLA mismatches (defined by serology for class 1 and molecular typing for DRB1).The donor was HLA mismatched in 96% of UCBT recipients, and in 41% of BMT recipients (P<0.001). Other significant differences were observed in preparative regimens, and graft-versus-host disease (GVHD) prophylaxis. Nonadjusted estimates of 2-year OS and DFS rates were 53% and 48% in the BMT group, and 33% and 25% in the UCBT group (P<0.001). However, 2-year OS and DFS rates in the standard group were not significantly different in the two groups (63% and 63% in the BMT group, and 75% and 58% in the UCBT group; p=0.98 and 0.32). Compared with BMT recipients, UCBT recipients had delayed hematopoietic recovery (Hazard ratio [HR]= 0.52; 95% confidence interval [95CI]: 0.36–0.75; p<0.001), increased 100 day TRM (HR=3.07; 95CI 1.45–6.51; p<0.01) and decreased grade II–IV acute graft-versus-host disease (aGVHD) (HR=0.58; 95CI 0.35–0.96; p=0.03). Two-year relapse rate was not significantly different in the two groups. <Conclusion> We conclude that UCBT from an unrelated donor is a therapeutic option for adult AML/MDS patients who lack an HLA-identical donors. Higher mortality, especially from non-relapse causes, is the biggest problem to be solved to increase the feasibility of this approach.

Constitutive Activation of SHP2 Protein Tyrosine Phosphatase Cooperates with HoxA10 Overexpression for Progression to Acute Myeloid Leukemia in a Murine Model

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 752-752
Author(s):  
Hao Wang ◽  
Stephan Lindsey ◽  
Iwona Konieczna ◽  
Elizabeth Horvath ◽  
Ling Bei ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Protein Tyrosine Phosphatase ◽  
Myeloid Leukemia ◽  
Tyrosine Phosphatase ◽  
Post Translational Modification ◽  
Protein Tyrosine ◽  
Acute Myeloid ◽  
Myeloid Progenitors

Abstract HOX genes encode highly conserved homeodomain (HD) transcription factors and are arranged in four groups (A–D). During definitive hematopoiesis, HOX gene expression is activated 3′ to 5′ through each group. Therefore, HOX1-4 are actively transcribed in hematopoietic stem cells and HOX7-11 in committed progenitors. Under normal conditions, HoxA7-11 expression decreases during CD34+ to CD34− maturation. Abnormal Hox expression is characteristic of several poor prognosis subtypes of Acute Myeloid Leukemia (AML) including AML with translocations or duplications of the MLL gene. In such leukemias, expression of HoxB3, B4 and A7-11 is sustained in CD34−CD38+ cells. In murine bone marrow transplantation experiments, expression of MLL fusion proteins, HoxA9 or HoxA10 induces a myeloproliferative disorder (MPD) characterized by increased neutrophils (PMN). Over time, the mice progress to AML with circulating myeloid blasts. These results suggest overexpression of HoxA9 or HoxA10 is adequate for MPD, but differentiation block (AML) requires additional lesions. We found that HoxA9 and HoxA10 proteins not only decrease in expression during the CD34+ to CD34− transition, but also are tyrosine phosphorylated. In additional studies, we found that HoxA10 tyrosine phosphorylation state is relevant for differentiation stage-specific target gene expression during myelopoiesis. HoxA10 represses genes encoding phagocyte effector proteins in undifferentiated myeloid cells. During myelopoiesis, phosphorylation of conserved HD-HoxA10 tyrosines decreases binding to these genes, permitting phenotypic and functional differentiation. HoxA10 activates transcription of the gene encoding Mkp2 (Dusp4) in myeloid progenitors. Decrease in HoxA10-binding to this gene as differentiation proceeds decreases transcription and renders the cells susceptible to Jnk induced apoptosis. Therefore, we hypothesized that genetic lesions which influence post translational modification might cooperate with HoxA10 overexpression to lead from MPD to AML. In myeloid progenitors, HoxA10 is maintained in a non-phosphorylated state by SHP2 protein tyrosine phosphatase. SHP2 activity decreases as differentiation proceeds. Activating mutations in SHP2 have been described in AML. We found that such activated SHP2 mutants dephosphorylate HoxA10 through out ex vivo myelopoiesis. Therefore, we investigated cooperation between these two leukemia associated abnormalities in vivo. Mice were transplanted with bone marrow overexpressing HoxA10 (or empty vector control) with or without activated SHP2 (E76K). To control for SHP2 overexpression, other mice were transplanted with bone marrow overexpressing HoxA10 and wild type SHP2. Mice transplanted with bone marrow overexpressing HoxA10 (±SHP2) developed MPD which evolved to AML over 4 mos, consistent with previous observations. However, mice transplanted with bone marrow overexpressing HoxA10 and E76K SHP2 developed AML within 4 wks. This rapid development of AML correlated with abnormalities in expression of myeloid specific HoxA10 target genes. These studies indicate the importance of HoxA10 post translational modification for physiologically relevant function and identify cooperating lesions which may be significant for disease progression in human AML.

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