Lpxn Regulates Proliferation, Adhesion and Invasion of Acute Myeloid Leukemic Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5095-5095
Author(s):  
Haiping Dai ◽  
Guohua Zhu ◽  
Qun Shen ◽  
Lili Wu ◽  
Qian Wang ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Mapk Pathway ◽  
Adaptor Protein ◽  
Leukemic Cells ◽  
Fusion Partner ◽  
Integrin Α4 ◽  
K 562 Cells ◽  
Adhesion And Invasion ◽  
Acute Myeloid

Abstract Leupaxin (LPXN) belongs to the focal adhesion-associated adaptor protein family, participating in regulating cell adhesion and metastasis. LPXN is a recurrent fusion partner in translocations identified in AML, namely t(11;12) and t(11;21), highlights its potential leukemogenic role in acute myeloid leukemia (AML). However, the precise mechanisms by which LPXN participate in the pathogenesis and progression of AML remains unknown. In the present study, we found that LPXN had a wide expression among a variety of hematological malignancies, including AML. Stable overexpression of LPXN in K-562 cells highlighted the proliferation advantage induced by this gene observed via colony-forming-assay and nude mice models. Proliferation was believed to be induced by LPXN-driven upregulation of ERK1/2 and pERK1/2 in K562-LPXN cells. Moreover, LPXN-expressing K-562 cells were less inhibited by arsenic trioxide, as compared with control cells, which might due to downregulation of BAX, FAS and upregulation of BCL-2. Adhesion to fibronectin and invasion across matrigel were modulated by overexpression and knockdown of LPXN, respectively. Similarly, activity of MMP-9 and MMP-2, and expression of integrin α4, α5 and β1, correlated with overexpression or silencing of LPXN, respectively. Expression of pP38 also showed a positive correlation with LPXN. In general, our data suggests that LPXN promotes proliferation in vitro and in vivo via the MAPK pathway, as well as enhances adhesion and invasion of AML cells through modulating expression of integrin α4, α5, β1 and MMP-9/MMP-2. Disclosures No relevant conflicts of interest to declare.

scholarly journals "Identification of Mechanisms By Which Mesenchymal Stem/Stromal Cells Contribute to Acute Myeloid Leukemia"

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5194-5194
Author(s):  
Allolo Aldreiwish ◽  
Gauri Muradia ◽  
Remi Gagne ◽  
Marc Beal ◽  
Carole Yauk ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stromal Cells ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
In Silico Analysis ◽  
Leukemic Cells ◽  
Silico Analysis ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a blood malignancy resulting in abnormal hematopoiesis that is reported to be associated with alterations in the bone marrow microenvironment (BME). Current treatments for this heterogeneous disease, which target the leukemic cells but not the BME, are largely unsuccessful for the majority of AML subtypes. By better understanding the mechanisms by which the BME contributes to leukemogenesis, it may be possible to introduce more effective treatments for AML. Mesenchymal stem cells (MSCs) are an essential component of the BME that have been shown to support normal hematopoiesis. Therefore, MSCs may have several roles in the alteration of the BME, leukemogenesis, and AML relapse and can provide an excellent model for studying the BME in vitro. While some studies have characterized AML-derived MSCs (AML-MSCs), their exact role in the disease remains unclear. Our RNAseq analysis of AML-MSCs (n=30), and healthy donor MSCs (HD-MSCs) (n=8) identified that, among 7655 genes, 21 genes were significantly differentially expressed in AML-MSCs. Through in silico analysis of this gene set, genes of interest were identified as having the potential to directly alter the BME and affect AML pathogenesis through BMP/TGF-β pathways. Current work is focusing on investigation of the effects of selected genes with biological relevance on MSCs intrinsic and extrinsic functional properties. This study will improve our understanding of the role of MSCs in AML BME and help in the discovery of new therapeutic targets. Disclosures No relevant conflicts of interest to declare.

CXCR4 Inhibitors Selectively Eliminate CXCR4 Expressing Human Acute Myeloid Leukemia Cells in NOG Mouse Model

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1881-1881
Author(s):  
Yanyan Zhang ◽  
Satyananda Patel ◽  
Monika Wittner ◽  
Stephane De Botton ◽  
Eric Solary ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Leukemic Cell ◽  
Cxcr4 Expression ◽  
Leukemic Cells ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

Abstract Abstract 1881 The chemokine receptor CXCR4 favors the interaction of acute myeloid leukemia (AML) cells with their niche but the extent to which it participates to pathogenesis is unclear. Here we show that CXCR4 expression at the surface of leukemic cells allowed distinguishing CXCR4high (25/47; 53%) from CXCR4neg/low (22/47, 47%) AML patients. Leukemic engraftment in NOD/Shi-scid/IL-2Rnull (NOG) mice was observed for both the CXCR4high and CXCR4neg/low groups. When high levels of CXCR4 are expressed at the surface of AML cells, blocking the receptor function with small molecule inhibitors could promote leukemic cell death and reduce NOG leukemia-initiating cells (LICs). Conversely, these drugs had no efficacy when AML cells do not express CXCR4 or when they do not respond to CXCL12. Mechanisms of this anti-leukemic effect included interference with the retention of LICs with their supportive bone marrow microenvironment niches, as indicated by a mobilization of LICs in response to drugs, and increased apoptosis of leukemic cells in vitro and in vivo. CXCR4 expression level on AML blast cells and their migratory response to CXCL12 are therefore predictive of the response to the inhibitors and could be used as biomarkers to select patients that could potentially benefit from the drugs. Disclosures: No relevant conflicts of interest to declare.

The PAF Complex Regulation of Prmt5 Facilitates Leukemic Progression

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3914-3914
Author(s):  
Justin Serio ◽  
Wei Chen ◽  
Maria Mysliwski ◽  
Lili Chen ◽  
James Ropa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Conflicts Of Interest ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Cytokine Signaling ◽  
Cycle Arrest ◽  
Acute Myeloid

Abstract Acute myeloid leukemias have been linked with dysregulated epigenetic landscapes sometimes attributed to altered functions of epigenetic regulators. The Polymerase-Associated Factor complex (PAFc) is an epigenetic regulator involved in transcriptional initiation, elongation and termination and directly interacts with the CTD of RNA Pol II. The complex is comprised of 6 subunits in human cells, Paf1, Cdc73, Ctr9, Leo1, Rtf1 and Ski8. Many of these subunits have key roles in a variety of cancers including acute myeloid leukemia (AML). We have previously shown the relevance of the PAFc in MLL-rearranged leukemias where its interaction with MLL fusion-proteins is required for leukemic progression in vitro and in vivo (Muntean et al. 2013 Blood, Muntean et al. 2010 Cancer Cell). However, little is known about the gene programs controlled by the PAFc and how these contribute to leukemogenesis. Here we identify Prmt5, an arginine methyltransferase, as a direct downstream target gene of the PAFc. Prmt5 is upregulated in variety of cancers and has been linked to cell cycle progression and activation of known oncoproteins. In addition, Prmt5 has been implicated in AML and is essential for normal hematopoiesis where loss of Prmt5 induces bone marrow aplasia due to impaired cytokine signaling (Tarighat et al. 2015 Leukemia, Liu et al. 2015 J Clin Invest). Our work establishes a major role for the PAFc in regulating Prmt5 expression in AML. We observe that excision of the Cdc73 subunit of the PAFc results in reduced proliferation, the induction of differentiation, cell cycle arrest, and a mild increase in apoptosis. Several key epigenetic marks are reduced globally upon loss of Cdc73 including H4R3me2s, a modification catalyzed by Prmt5. RNA sequencing and bioinformatics analysis using GSEA, revealed that loss of Cdc73 led to increased expression of a gene program associated with hematopoietic differentiation, in agreement with our cellular characterization. In addition, the downregulation of a methyltransferase gene program was detected upon Cdc73 excision. Included in this signature were several members of the Prmt family. Analysis of changes in expression following loss of Cdc73 and functional relevance in MLL-AF9 leukemic cells led us to Prmt5 as a gene critically important in AML cells and modulated by the PAFc. To interrogate the function of Prmt5 in AML cells, we performed shRNA knockdown experiments which resulted in reduced proliferation, reduced cell fitness, G1 cell cycle arrest and global reduction H4R3me2s. ChIP experiments revealed that the PAFc localizes to the Prmt5 locus in mouse and human derived leukemic cells. Further, preliminary data suggests the MLL-AF9 fusion protein also localizes to the Prmt5 locus and may enhance its transcriptional output. The enzymatic activity of Prmt5 is necessary for AML cell growth as wild type PRMT5 can rescue proliferation of Prmt5 knock-down cells while a catalytic dead mutant cannot. Furthermore, we have observed that knockdown of Prmt5 increases the disease latency of Hoxa9/Meis1 induced leukemia in vivo. Utilizing a commercially available inhibitor for Prmt5, EPZ015666 (Chan-Pembre et al. 2015 Nat Chem Bio), we show pharmacologic inhibition of PRMT5 reduces the growth of a spectrum of human leukemic cell lines, suggesting PRMT5 is important for multiple subtypes of AML. Overall, our findings elucidate the PAFc as a regulator of Prmt5 expression that is necessary for the maintenance of AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals Extracellular ATP and CD39 Regulates Mitochondrial Function and Cytarabine Resistance through Intrinsic PKA-ATF-PGC1a Pathway in Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2737-2737
Author(s):  
Jean-Emmanuel Sarry ◽  
Christian Recher ◽  
Nesrine Aroua
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Leukemic Cells ◽  
Nucleoside Triphosphate ◽  
Preclinical Model ◽  
Acute Myeloid

Abstract Relapses in acute myeloid leukemia (AML) are caused by chemoresistant leukemic populations and new therapeutic approaches that specifically target these cells are urgently needed. Based on transcriptomic analyses of relevant PDX preclinical model of the resistance to cytarabine (AraC) and of the residual disease in patients, we identified ecto-nucleoside triphosphate diphosphohydrolase-1 CD39 (ENTPD1) overexpressed in the residual leukemic cells in vivo after chemotherapy. By flow cytometry, we confirmed that AraC increased cell surface CD39 expression in AML cell lines in vitro and in vivo as well as in 24 diverse patient-derived xenograft models. We further observed this increase in 100 patients at 35-days post-intensive chemotherapy compared to their respective diagnosis. Interestingly, high CD39 expression on AML patients was associated with a worse response to AraC in vivo. Furthermore, we showed that FACS-sorted CD39high AML cells had increased mitochondrial mass and activity, and were resistant to AraC in vitro and in vivo. We demonstrated that CD39 downstream signaling pathway was dependent on cAMP-PKA-PGC1a-TFAM axis and its inhibition by H89 sensitized AML cells to AraC through the inhibition of mitochondrial OxPHOS biogenesis and function. Finally, pharmacological inhibition of CD39 ATP hydrolase activity or genetic invalidation of CD39 protein using two inhibitors or shRNA markedly enhanced AraC cytotoxicity in AML cell lines and primary patient samples in vitro and in vivo. Together, these results indicate CD39 as a new player of the intrinsic chemoresistance pathway and a new therapeutic target to specifically overcome AraC resistance and eradicate these leukemic cells responsible for relapses in AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals Long Noncoding RNA HOXA-AS2 As a Predictor of Acute Myeloid Leukemia: Clinical Association between HOXA-AS2 Expression and Its Role in Leukemic Cell Growth

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5131-5131
Author(s):  
Xiaojing Yan ◽  
Yi Qu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Noncoding Rna ◽  
Conflicts Of Interest ◽  
In Vitro Study ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
G0 Phase ◽  
Acute Myeloid

Abstract Long noncoding RNAs (lncRNAs) have important roles in diverse cellular processes and carcinogenesis. Homeobox (HOX)A cluster antisense RNA 2 (HOXA-AS2) is a 1048-bp lncRNA located between human HOXA3 and HOXA4 genes whose overactivation was previously found to promote the proliferation and invasion of solid tumors. However, its biological roles in acute myeloid leukemia (AML) remain unclear. This study showed that HOXA-AS2 was overexpressed in patients with AML. In addition, the increased HOXA-AS2 expression level correlated with higher white blood cell and bone marrow (BM) blast counts, unfavorable karyotype classification, earlier death, and inferior survival of patients with AML. Moreover, the results of an in vitro study showed that the silencing of HOXA-AS2 significantly inhibited the growth of leukemic cells through inducing G1/G0 phase arrest and apoptosis. In conclusion, these findings suggested that HOXA-AS2 functioned as an oncogene and might be a useful biomarker for diagnosis and prognostic prediction in patients with AML, providing a promising therapeutic target for AML. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mitochondrial Spare Reserve Capacity : A New Predictive Metabolic Biomarker for Aggressiveness of Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-7
Author(s):  
Quentin Fovez ◽  
Bruno Quesnel ◽  
William Laine ◽  
Raeeka Khamari ◽  
Celine Berthon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Oxygen Consumption ◽  
Oxidative Phosphorylation ◽  
Mutation Rate ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Reserve Capacity ◽  
Glycolytic Activity ◽  
Acute Myeloid

Introduction The persistence of leukemic cells after treatment limits the effectiveness of anticancer drugs and is the cause of relapse in patients with acute myeloid leukemia (AML). After exposure to chemotherapeutic drugs, the survival of leukemic cells is mainly supported by mitochondrial energy metabolism. Several preclinical studies have shown that the combination of mitochondrial oxidative phosphorylation inhibitors with various anticancer treatments constitutes an effective therapeutic combination in vitro to eradicate the surviving leukemic cells. Evaluating the mitochondrial bioenergetic activity of blasts from AML patients could therefore provide predictive information on treatment response. The basal oxygen consumption of cells varies according to hematopoietic differentiation and depends on the energy needs in the in vitro condition of measurement. But it is necessary to treat the cells with uncoupling agents (eg FCCP) to assess the maximum activity that the respiratory chain could reach to respond to energy stress. Then, the switch from a basal level of oxygen consumption to a maximum level defines the mitochondrial spare reserve capacity (SRC). In this study, we propose to determine whether spare reserve capacity of blasts is a potential biomarker of AML aggressiveness in patients and to characterize the biochemical processes involved in the control of SRC in leukemic cells. Results Using the XFe24 Seahorse fluorometric oximeter, we first determined the mitochondrial oxygen consumption and glycolytic activity in hematopoietic cells (monocytes, lymphocytes, dendritic cells) of healthy donors, in AML patient blasts at diagnosis or at relapse and in AML cell lines (HL-60, MOLM-13, THP-1, KG1, OCI-AML3, MV-4-11, U-937). All measures have been assessed from freshly collected samples of peripheral blood and of bone marrow. As expected, AMLs are characterized by low oxidative phosphorylation activity compared to normal hematopoietic cells. From all the OXPHOS values obtained we defined a SRC threshold above which the SRC is considered high. This threshold has been set at a capacity to increase basal respiration by 250%. From patients blasts, we have therefore defined two groups characterized by high (n=14) or low (n=21) mitochondrial spare reserve capacity. Blasts with high SRC exhibit high glycolytic activity suggesting a link between spare reserve capacity and glucose metabolism. Using U-13C6 glucose and pharmacological inhibitors, we have demonstrated that the utilization of the mitochondrial spare reserve capacity of leukemic cells is supported through glycolysis and that mitochondrial oxidation of pyruvate is a key element for SRC recruitment. Mitochondrial pyruvate carrier inhibitors (as UK-5099) or gene silencing of BRP44 abolish the SRC of leukemic cells highlighting the importance of pyruvate oxidation to increase oxygen consumption. Since high mutation rate is recognized as an unfavorable prognostic factor in AML, we have also sequenced 45 commonly genes mutated in AMLs characterized by high or low SRC blasts. Interestingly, DNA sequencing analysis showed that AML with low SRC blasts have a higher mutation rate than high SRC blasts and also exhibited exclusive mutations such as ASXL1 (25%), IDH2 (25%), NPM1 (25%), IDH1 (13%), JAK2 (13%) and SF3B1 (13%). Conclusion Currently, most of the clinical biomarkers used to predict AML aggressiveness are based on DNA analysis, but the emergence of mutations is not always associated with phenotypic changes. This study shows that the mitochondrial spare reserve capacity of blasts represents a new functional biomarker based on the assessment of the energetic phenotype and could help the clinicians to determine the prognosis of AML. Moreover we have showed that altering pyruvate metabolism highly decrease spare reserve capacity of blasts and then could be evaluated as metabolic strategies to improve the therapeutic response in patients with AML. Disclosures Kluza: Daiichi-Sankyo: Research Funding.

scholarly journals Effects of novel retinoid X receptor-selective ligands on myeloid leukemia differentiation and proliferation in vitro

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1977-1984 ◽  
Author(s):  
M Kizaki ◽  
MI Dawson ◽  
R Heyman ◽  
E Elster ◽  
R Morosetti ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Clonal Growth ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Synergistic Effects ◽  
Leukemic Cells ◽  
Acute Myeloid Leukemia Cells ◽  
Differentiation And Proliferation ◽  
Acute Myeloid

The biologic effects of retinoids such as all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid on proliferation and differentiation of hematopoietic cells are mediated by binding and activating two distinct families of transcription factors: the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). The RARs require heterodimerization with RXRs; in addition, RXRs can form homodimers, which can bind to DNA response elements that are either distinct or the same as those bound by the RAR/RXR heterodimers. Therefore, the two retinoid pathways provide sequences that are specific for effective DNA binding and activation of target genes. We have developed several series of novel synthetic retinoids that selectively interact with RXR/RXR homodimers and RAR/RXR heterodimers. We show here that SR11236 and SR11246, which are RXR-selective analogs, had little ability to inhibit clonal growth and induce differentiation of leukemic cells (HL- 60 cells and fresh acute myeloid leukemia cells). However, SR11249, SR11256, and LGD1069, which activated both RXR/RXR homodimers and RAR/RXR heterodimers, could inhibit clonal growth and induce differentiation of HL-60 cells as well as leukemic cells from patients, including those with acute promyelocytic leukemia (APL). This is similar to results observed with RAR/RXR-specific ligands. Interestingly, the combination of ATRA and either SR11249, SR11256, or LGD1069 showed synergistic effects in inducing differentiation of HL-60 cells. A retinoid (SR11238) with strong anti-AP-1 activity that did not activate the RARs and RXRs for gene transcription from the response element TREpal was inactive in our assay systems, suggesting that the antiproliferative effects of retinoids on leukemic cells is not mediated by inhibiting the AP-1 pathway. We conclude that the RAR/RXR pathway is more important than RXR/RXR pathway for differentiation and proliferation of acute myeloid leukemic cells, and certain retinoids or combination of retinoids with both RAR and RXR specificities may synergistically enhance the differentiation activity of ATRA, which may be relevant in several clinical situations.

scholarly journals Anti-MY9-blocked-ricin: an immunotoxin for selective targeting of acute myeloid leukemia cells

Blood ◽  
1991 ◽  
Vol 77 (11) ◽  
pp. 2404-2412 ◽  
Author(s):  
DC Roy ◽  
JD Griffin ◽  
M Belvin ◽  
WA Blattler ◽  
JM Lambert ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Leukemic Cells ◽  
Short Exposure ◽  
Continuous Exposure ◽  
Dependent Manner ◽  
Acute Myeloid

Abstract The use of immunotoxins (IT) to selectively destroy acute myeloid leukemia (AML) cells in vivo or in vitro is complicated by both the antigenic similarity of AML cells to normal progenitor cells and the difficulty of producing a sufficiently toxic conjugate. The monoclonal antibody (MoAb) anti-MY9 is potentially ideal for selective recognition of AML cells because it reacts with an antigen (CD33) found on clonogenic AML cells from greater than 80% of cases and does not react with normal pluripotent stem cells. In this study, we describe an immunotoxin that is selectively active against CD33+ AML cells: Anti- MY9-blocked-Ricin (Anti-MY9-bR), comprised of anti-MY9 conjugated to a modified whole ricin that has its nonspecific binding eliminated by chemical blockage of the galactose binding domains of the B-chain. A limiting dilution assay was used to measure elimination of HL-60 leukemic cells from a 20-fold excess of normal bone marrow cells. Depletion of CD33+ HL-60 cells was found to be dependent on the concentration of Anti-MY9-bR and on the duration of incubation with IT at 37 degrees C. More than 4 logs of these leukemic cells were specifically depleted following short exposure to high concentrations (10(-8) mol/L) of Anti-MY9-bR. Incubation with much lower concentrations of Anti-MY9-bR (10(-10) mol/L), as compatible with in vivo administration, resulted in 2 logs of depletion of HL-60 cells, but 48 to 72 hours of continuous exposure were required. Anti-MY9-bR was also shown to be toxic to primary AML cells, with depletion of greater than 2 logs of clonogenic cells following incubation with Anti- MY9-bR 10(-8) mol/L at 37 degrees C for 5 hours. Activity of Anti-MY9- bR could be blocked by unconjugated Anti-MY9 but not by galactose. As expected, Anti-MY9-bR was toxic to normal colony-forming unit granulocyte-monocyte (CFU-GM), which expresses CD33, in a concentration- and time-dependent manner, and also to burst-forming unit-erythroid and CFU-granulocyte, erythroid, monocyte, megakaryocyte, although to a lesser extent. When compared with anti-MY9 and complement (C′), Anti- MY9-bR could be used in conditions that provided more effective depletion of AML cells with substantially less depletion of normal CFU- GM. Therefore, Anti-MY9-bR may have clinical utility for in vitro purging of AML cells from autologous marrow when used at high IT concentrations for short incubation periods. Much lower concentrations of Anti-MY9-bR that can be maintained for longer periods may be useful for elimination of AML cells in vivo.

Selective Ablation of Acute Myeloid Leukemia Using Antibody-Targeted Chemotherapy: A Phase I Study of an Anti-CD33 Calicheamicin Immunoconjugate

Blood ◽  
1999 ◽  
Vol 93 (11) ◽  
pp. 3678-3684 ◽  
Author(s):  
E.L. Sievers ◽  
F.R. Appelbaum ◽  
R.T. Spielberger ◽  
S.J. Forman ◽  
D. Flowers ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
High Rate ◽  
Leukemic Cells ◽  
Antitumor Antibiotic ◽  
Dose Escalation Study ◽  
Hematopoietic Stem ◽  
Selective Ablation ◽  
Acute Myeloid

Abstract Leukemic blast cells express the CD33 antigen in most patients with acute myeloid leukemia (AML), but this antigen is not expressed by hematopoietic stem cells. We conducted a study to determine whether normal hematopoiesis could be restored in patients with AML by selective ablation of cells expressing the CD33 antigen. In a dose escalation study, 40 patients with relapsed or refractory CD33+ AML were treated with an immunoconjugate (CMA-676) consisting of humanized anti-CD33 antibody linked to the potent antitumor antibiotic calicheamicin. The capacity of leukemic cells to efflux 3,3’-diethyloxacarbocyanine iodide (DiOC2) was used to estimate pretreatment functional drug resistance. Leukemia was eliminated from the blood and marrow of 8 (20%) of the 40 patients; blood counts returned to normal in three (8%) patients. A high rate of clinical response was observed in leukemias characterized by low dye efflux in vitro. Infusions of CMA-676 were generally well tolerated, and a postinfusion syndrome of fever and chills was the most common toxic effect. Two patients who were treated at the highest dose level (9 mg/m2) were neutropenic >5 weeks after the last dose of CMA-676. These results show that an immunoconjugate targeted to CD33 can selectively ablate malignant hematopoiesis in some patients with AML.

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