CD34+/CD38− Acute Myelogenous Leukemia Cells Aberrantly Express Aurora Kinase A

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1886-1886
Author(s):  
Jing Yang ◽  
Takayuki Ikezoe ◽  
Mutsuo Furihata ◽  
Chie Nishioka ◽  
Akihito Yokoyama
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Specific Inhibitor ◽  
Aurora Kinase ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
Aurora Kinase A ◽  
Acute Myelogenous ◽  
Kinase A

Abstract Abstract 1886 Aurora kinase A (AURKA) plays a pivotal role in the mitotic processes during cell division. We previously showed that AURKA was aberrantly expressed in hematological malignant cells including those from acute myelogenous leukemia (AML) and acute lymphoblastic leukemia, compared with CD34+ hematopoietic stem/progenitor cells isolated from healthy volunteers. This study found that freshly isolated CD34+/CD38− cells from individuals with AML (n=12) in which leukemia stem cells were supposed to be enriched expressed a greater amount of AURKA than their CD34+/CD38+ counterparts, as measured by real time RT-PCR. Blockade of AURKA by the specific inhibitor MLN8237 significantly inhibited proliferation and induced apoptosis of CD34+/CD38− AML cells, as assessed by the clonogenic assay and detection of the cleaved form of poly (ADP-ribose) polymerase by Western blot analysis, respectively. In addition, exposure of CD34+/CD38− AML cells to MLN8237 down-regulated levels of Bcl-2 family proteins and increased Bax/Bcl-2 expression ratio. Moreover, inhibition of AURKA by MLN8237 (30mg/kg for 14 consecutive days) impaired engraftment of CD34+/CD38− AML cells in severely immunocompromised mice (n=5, 49±32% in control vs 18±16% in MLN8237 treated mice, P<0.05), and prolonged their overall survival (P<0.05), compared with vehicle treated mice. Taken together, AURKA may be a promising molecular target to eliminate chemotherapy-resistant CD34+/CD38− AML cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CD34+/CD38−acute myelogenous leukemia cells aberrantly express Aurora kinase A

2013 ◽  
pp. n/a-n/a ◽  
Author(s):  
Jing Yang ◽  
Takayuki Ikezoe ◽  
Chie Nishioka ◽  
Atsuya Nobumoto ◽  
Keiko Udaka ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Aurora Kinase ◽  
Myelogenous Leukemia ◽  
Leukemia Cells ◽  
Aurora Kinase A ◽  
Acute Myelogenous ◽  
Kinase A

Sequential Acquisition of AML1-ETO and c-Kit Mutation Leads to Formation of Human t(8;21) Acute Myelogenous Leukemia Stem Cells,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3584-3584
Author(s):  
Takahiro Shima ◽  
Yoshikane Kikushige ◽  
Toshihiro Miyamoto ◽  
Koichi Akashi
Keyword(s):  
Stem Cells ◽  
Acute Myelogenous Leukemia ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Myelogenous Leukemia ◽  
Target Cells ◽  
Hematopoietic Stem ◽  
Kit Mutation ◽  
Acute Myelogenous

Abstract Abstract 3584 The 8;21 translocation, one of the most general chromosomal abnormalities in acute myelogenous leukemia (AML), encodes the AML1-ETO chimeric fusion gene. Because AML1-ETO can inhibit the CBF complex to transactivate myeloid-lineage genes in a dominant negative fashion, the high level expression of this gene plays a critical role in inhibiting differentiation of target cells, which leads to progression of AML. We, however, have reported that patients maintaining a long-term remission retain AML1-ETO expression at a very low level that can be detected by nested RT-PCR. The AML1-ETO transcripts in these patients were derived from a small fraction of t(8;21)+ hematopoietic stem cells (HSCs) capable of multilineage differentiation (PNAS 2000). In fact, previous data shown that AML1/ETO knock-in or AML1/ETO transgenic mice did not develop AML. These data suggest that acquisition of the AML1-ETO fusion is not sufficient to develop t(8;21) AML. Since t(8;21) AML cells frequently possess constitutive active mutation of c-Kit, we hypothesized that the c-Kit mutation may work as a second oncogenic hit in t(8;21)+ HSCs to transform into AML. To test the hypothesis, we extensively analyzed the existence of c-Kit mutation within AML1-ETO+ HSCs from patients maintaining remission for a long-term. CD34+CD38− HSCs were purified from the bone marrow of patients in long-term remission, and were cultured in vitro to form colonies. These HSC-derived colonies were picked up, and tested for the presence ofAML1-ETO and c-Kit mutation. Five t(8;21) AML patients with c-Kit mutation were enrolled in this study. All of 1020 blastic colonies at diagnosis were positive for both AML1-ETO and c-Kit mutation. In 7187 colonies formed in the culture of remission marrow, almost 1% (89 colonies) of these colonies expressed AML1-ETO. Surprisingly, none of these colonies possessed c-Kit mutation, indicating that AML1-ETO+ clones in remission are not identical to these in t(8;21) AML. Accordingly, it is highly likely that HSCs first acquire AML1-ETO, and a fraction of these cells additionally mutated c-Kit, resulting in transformation into AML stem cells. This is the first clear-cut evidence that human HSCs transform into AML via multi-step oncogenesis in vivo. Disclosures: No relevant conflicts of interest to declare.

Development of a Novel Treatment Strategy Targeting JAK2 in Acute Myelogenous Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2619-2619
Author(s):  
Shinsuke Kojima ◽  
Takayuki Ikezoe ◽  
Jing Yang ◽  
Chie Nshioka ◽  
Asako Takeuchi ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Conflicts Of Interest ◽  
Remission Rate ◽  
Hematopoietic Cells ◽  
Rare Event ◽  
Specific Inhibitor ◽  
Janus Kinase ◽  
Myelogenous Leukemia ◽  
Jak2 Inhibitor ◽  
Acute Myelogenous

Abstract Abstract 2619 Poster Board II-595 Somatic mutations in Janus kinase 2 (JAK2) gene activate JAK2/signal transducer and activator of transcriptions (STATs) signaling, leading to proliferation of hematopoietic cells. STAT3 and/or STAT5 were constitutively activated in the majority of patients with acute myelogenous leukemia (AML), although mutation of the JAK2 gene was an extremely rare event in AML. This study performed the immunohistochemichal examination to verify whether JAK2 was activated in AML (n=73, excluding acute promyelocytic leukemia) by utilizing the phosphor-specific antibody against JAK2. p-JAK2 was detectable in all cases examined, although its level varied between each patients (+, n=27; +/−, n=28; −/+, n=18). Statistical examination found that levels of p-JAK2 were correlated with leukocytosis (21.4 × 106/L in patients with high p-JAK2 vs 13.8 × 106/L in those with low p-JAK2, p<0.001) and lower complete remission rate (65.5% in patients with high p-JAK2 vs 83.3% in patients with low p-JAK2, p<0.02). In addition, there was a trend that high expression level of p-JAK2 was associated with poor prognosis in AML patients (median survival time 604 days in patients with high p-JAK2 vs 1431 days in those with low p-JAK2). Moreover, we found that the novel and specific inhibitor of the JAK2 kinase AZ960 potently inhibited the clonogenic growth of freshly isolated CD34+ AML cells from patients (n=6) with IC50 ranging from 0.01 to 0.1 mM. On the other hand, levels of p-JAK2 in CD34+ hematopoietic cells from healthy volunteers (n=3) were lower than those in CD34+AML cells, as measured by FACS, and their colony forming ability was not affected by AZ960. Furthermore, exposure of freshly isolated CD34+ AML cells to AZ960 (0.03–0.1 mM) induced apoptosis as assessed by induction of the cleaved forms of PARP as well as caspase 3, and downregulation of anti-apoptotic protein Bcl-xL. Taken together, JAK2 may be a promising molecular target for treatment of AML. Further studies are warranted to evaluate the efficacy of the JAK2 inhibitor in clinical settings. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes

Blood ◽  
2005 ◽  
Vol 105 (12) ◽  
pp. 4878-4884 ◽  
Author(s):  
Katharine C. Hsu ◽  
Carolyn A. Keever-Taylor ◽  
Andrew Wilton ◽  
Clara Pinto ◽  
Glenn Heller ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Activity ◽  
Disease Free Survival ◽  
Myelogenous Leukemia ◽  
Target Cells ◽  
Hematopoietic Stem ◽  
Hla Ligand ◽  
Acute Myelogenous

Abstract Inhibitory killer immunoglobulin (Ig)-like receptors (KIRs) recognize HLA-C and -B epitopes on target cells, thereby regulating natural killer (NK) cell activity. In 178 patients receiving T-cell-depleted HLA-identical sibling transplants for acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS), analysis of donor KIR genotype with HLA genotype demonstrated that 62.9% of the patients lacked an HLA ligand for donor-inhibitory KIR. Lack of HLA ligand for donor-inhibitory KIR (missing KIR ligand) had no effect on disease-free survival (DFS), overall survival (OS), or relapse in patients receiving transplants for CML and ALL. In patients with AML and MDS, however, there was a significant missing KIR ligand effect on DFS (P = .014; hazard ratio [HR], 0.53; 95% confidence interval [95% CI], 0.28-0.88) and OS (P = .03; HR, 0.53; 95% CI, 0.3-0.93). Incidence of relapse was also lower in patients with AML and MDS who lacked the HLA ligand for donor-inhibitory KIR (P = .04; HR, 0.41; 95% CI, 0.18-0.97). AML and MDS patients lacking 2 HLA ligands for donor-inhibitory KIR had the highest DFS (P = .002) and OS (P = .003). There was no significant contribution of donor-activating KIR to transplantation outcome in these patients. These data indicate that the absence of class I ligand in the recipient for donor-inhibitory KIR can be a prognostic factor for transplantation outcome in HLA-identical sibling transplantation and that the lack of HLA-C or -B ligands for donor-inhibitory KIR can contribute to improved outcomes for patients with AML and MDS. (Blood. 2005;105:4878-4884)

Marrow irradiation with high-dose 153Samarium-EDTMP followed by chemotherapy and hematopoietic stem cell infusion for acute myelogenous leukemia

2006 ◽  
Vol 47 (8) ◽  
pp. 1583-1592 ◽  
Author(s):  
Vilmarie Rodriguez ◽  
Peter M. Anderson ◽  
Mark R. Litzow ◽  
Linda Erlandson ◽  
Barbara A. Trotz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Acute Myelogenous

scholarly journals Immunophenotypic study of acute leukemia by flow cytometry at BPKMCH.

2013 ◽  
Vol 3 (5) ◽  
pp. 345-350
Author(s):  
S Shrestha ◽  
J Shrestha ◽  
CB Pun ◽  
T Pathak ◽  
S Bastola ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Acute Leukemia ◽  
Acute Myelogenous Leukemia ◽  
Lymphoblastic Leukemia ◽  
Bone Marrow Examination ◽  
Myelogenous Leukemia ◽  
Female Ratio ◽  
Flow Cytometric ◽  
Male Female Ratio ◽  
Acute Myelogenous

Background: Immunophenotyping of acute leukemia is one of the most important clinical applications of fl ow cytometry. The aim of this study was to determine the immunophenotyping profi le of acute leukemia, by means of a fl ow cytometric method, using monoclonal antibodies all marked with a fl uorochrome, in four colour systems to assess their distribution according to type of leukemia (lymphoid B or T / myeloid). Materials and Methods: We retrospectively collected data of immunophenotyping from 52 acute leukemia patients at the department of pathology in B.P. Koirala Memorial Cancer Hospital from January 2010 to December 2011. Diagnosis was based on peripheral blood and bone marrow examination for morphology, cytochemistry and immunophenotypic studies. Results: Out of total 52 cases of acute leukemia diagnosed by fl ow cytometry over a two year period, there were 31 cases (59.6 %) of acute lymphoblastic leukemia, 20 cases (38.4 %) of acute myelogenous leukemia and one case (1.9 %) of bi-phenotypic acute leukemia. Leukemia was diagnosed among adults in 44.2 % whereas among children with age less than or equal to 15 years in 55.7 %. Thirty eight (73%) were male and 14 (27 %) were female with a male: female ratio of 2.7:1. For acute myelogenous leukemia, it was found that M0 (5.0 %), M1 (20%), M2 (60%), M3 (15%), M4 (5.0 %) were detected. CD13 and CD33 were the most useful markers in the diagnosis of acute myelogenous leukemia. The most common subtype was AML-M2. Of the 31 cases with acute lymphoblastic leukemia, 20 cases (64.5 %) were identifi ed as B-ALL and 11 cases (35.5%) as T-ALL. Aside from cytoplasmic CD3 (cCD3) and CD7 were the most sensitive antigens present in all cases of T-ALL. All cases of B-ALL showed expression of pan B-cell markers CD19 and CD22, but 15 (75 %) of 20 cases expressed CD10. Conclusion: Flow cytometric immunophenotyping was found to be especially useful in the correct identifi cation and diagnosis of acute myeloid or lymphoblastic leukemia and its subtypes. In combination with French-American-British (FAB) morphology and immunophenotyping, we were able to diagnose and classify all patients with acute leukemia in this study. Journal of Pathology of Nepal (2013) Vol. 3, No.1, Issue 5, 345-350 DOI: http://dx.doi.org/10.3126/jpn.v3i5.7856

Sign in / Sign up

Export Citation Format

Share Document