Phenotypic Aberrations of Myeloid CD34+ Cells in Patients with Myelodysplastic Syndrome (MDS): Clinical Significance and Correlation with Cytogenetics Abnormalities.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2374-2374
Author(s):  
Dolores Subira ◽  
Patricia Font ◽  
Eva Arranz ◽  
Ramiro B Soraya ◽  
Susana Castanon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Fish Analysis ◽  
Aberrant Expression ◽  
Number Of Patients ◽  
Cd34 Cells ◽  
Design And Methods ◽  
Acute Myeloid

Abstract Expression of abnormal markers in myeloid CD34+ cells of patients with MDS is common, but few immunophenotypic data have been compiled so far. Based on the statement that CD7 and TdT are markers associated with a bad prognosis in acute myeloid leukemia, we intended to describe the incidence of their aberrant expression in CD34+ cells and its role helping to establish the diagnosis of MDS. OBJECTIVES: To explore the aberrant expression of TdT and CD7 in myeloid CD34+ cells of MDS patients and to describe their possible correlation with cytogenetic features. DESIGN AND METHODS: Bone marrow specimens from 45 patients with MDS were included in this study (17 RA, 12 RARS, 5 CMML, 9 RAEB, 2 RAEB-t). In addition, we analyzed 28 samples of bone marrow from patients with cytopenias, but no diagnosis of MDS, as a cohort control. Immunophenotyping was performed with the following combination of monoclonal antibodies: TdT FITC / CD7 PE/ CD34 PCy-5. A case was regarded as positive for any of these markers when their expression was described in at least, 25% of myeloid CD34+ cells. Besides, adequate cytogenetic data and FISH analysis of chromosomes 5, 7 and 8 were obtained from 42 out of the 45 MDS samples. RESULTS: The percentage of CD34+ myeloid cells in MDS samples was fewer than 2% in 25 cases, ranged from 2–5% in 6 cases and was equal or greater than 5% in 14 cases. Aberrant expression of CD7 and/or TdT was observed in 28 cases: 20 were positive for CD7, 5 cases were positive for TdT and co-expression of both antigens was described in 3 cases. Prevalence of these abnormal markers was much higher in patients with MDS (28/45; 62%) than in the cohort control (2/28; 7%) . Besides, we identified at least one abnormal marker in 14 of the 16 patients with high risk MDS (9 RAEB, 5 CMML, 2 RAEB.t). According to the IPSS, karyotypes were divided into subgroups of favorable, intermediate or unfavorable, being classified 29 patients with favorable karyotypes and 13 patients with no favorable cytogenetics. In the first group, the abnormal expression of CD7 and/or TdT was detected in 13/29 patients (44.8%) and in 10/13 patients in the non-favourable group (76.9%). CONCLUSIONS: CD7 and/or TdT expression in myeloid CD34 + cells may be helpful in establishing the diagnosis of MDS. Prevalence of these aberrancies seems to be higher in cases with no favorable karyotypes, but a larger number of patients will be required to state significant differences. Possible correlation between high risk MDS patients and immunophenotypic aberrancies suggests the convenience of following the outcome of those low risk MDS patients who have expression of any of these abnormal markers.

Treatment of Acute Myeloid Leukemia in a Community Hospital.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4575-4575
Author(s):  
Mandeep S. Dhami ◽  
Anca Bulgaru ◽  
Kandhasamy Jagathambal ◽  
Dinesh Kapur ◽  
Dennis E. Slater ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Community Hospital ◽  
Care Center ◽  
Tertiary Care ◽  
Cell Transplant ◽  
Number Of Patients ◽  
Acute Myeloid

Abstract Optimal management of patients with acute myeloid leukemia requires an accurate diagnosis along with cytogenetics and an intensive systemic chemotherapy regimen administered by a multidisciplinary team of experienced physicians, nurses and other support staff. It has been suggested that such complex patients should be treated only at tertiary care centers. However, it is often difficult for patients and families to receive care at teratiary care center which may be at a great distance from their home. Here we present a retrospective review of all patients diagnosed and treated for acute myeloid leukemia at William W Backus Hospital, a 213 bed acute care hospital serving a community of 70,000 in Norwich, Connecticut between the years 2000 and 2005. A total of 44 patients were treated during this period. There were 22 males and 22 females. The median age was 67.5 years. Bone Marrow samples were evaluated by a hematopathologist (histopathology, flowcytometry and cytogenetics) at a near-by tertiary care center. FAB subgroups and cytogenetics were similar to other published studies. APML patients are not included in this analysis. The median survival for the entire group was 14.7 months ranging from 2 days to 113 months. Fourteen patients were alive, all in continued clinical remission except one with relapsed disease and one patient remains transfusion dependent. Median survival was 15.2 months for men compared to 13.2 months for women. Four patients were referred for bone marrow/stem cell transplant after induction therapy. The limitation of this study is the relatively small number of patients as one would expect from a study done at a small community hospital. Nevertheless, it appears that the median survival of our patients is similar to a pooled analysis of five SWOG trials published by Gundacker et al. We conclude that most patients with acute myeloid leukemia can be managed in a community hospital with commitment and experience to treat such patients. Treatment outcomes (median survival) Study Number of Patients Under 55 55 – 65 65 – 75 Over 75 *Gundacker et al. Blood, 1 May 2006, volume 107, 3481–3485 Current study 44 17.1 m 18 m 11.7 m 5.7 m Gundacker et al* 968 18.8 m 9.0 m 6.9 m 3.5 m

Flt3 Receptor Inhibition Abolishes Constitutive NFκB Activation in High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2434-2434
Author(s):  
Jennifer Grosjean ◽  
Lionel Ades ◽  
Simone Bohrer ◽  
Pierre Fenaux ◽  
Guido Kroemer
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Plasma Membrane ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Constitutive Activation ◽  
Nf Kappab ◽  
Acute Myeloid

Abstract High-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are characterized by the constitutive activation of the anti-apoptotic transcription factor NF-kappaB, via the activation of the IKK complex. We show that constitutive activation of the receptor tyrosine kinase Flt3 is responsible for IKK activation and this activation of the NF-kappaB pathway was found to involve a not yet described phosphorylation of the IKK and IkBa complex involving tyrosine residues compared to serine residues in the classical NF-kappaB pathway. Chemical inhibition or knockdown of Flt3 with small interfering RNAs abolished NF-kappaB activation in MDS and AML cell lines, as well as in primary CD34+ bone marrow cells from patients, causing mitochondrial apoptosis. Epistatic analysis involving the simultaneous inhibition of Flt3 and IKK indicated that both kinases act via the same anti-apoptotic pathway. An IKK2 mutant with a constitutive kinase activity and a plasma membrane-tethered mutant of NEMO that activates IKK1/2 prevented the cytocidal action of Flt3 inhibition. IKK2 and Flt3 physically associated in MDS and AML cells and Flt3 inhibition caused the release of IKK2 from a preferential association with the plasma membrane. Flt3 inhibition only killed CD34+ bone marrow cells from high-risk MDS and AML patients, in correlation with the blast numbers and the NF-kappaB activity, yet had no lethal effect on healthy CD34+ cells or cells from low-risk MDS. These results suggest that Flt3 inhibitors might exert an anti-neoplastic effect in high-risk MDS and AML through inhibition of constitutive NF kappaB activation.

Immunophenotyping Features in Acute Myeloid Leukemia (AML) with NPM1+ and/or FLT3+

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4908-4908
Author(s):  
Pervin Topcuoglu ◽  
Klara Dalva ◽  
Sinem Civriz Bozdag ◽  
Onder Arslan ◽  
Muhit Ozcan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Leukemic Cells ◽  
Aberrant Expression ◽  
Hla Dr ◽  
Cd36 Expression ◽  
Cd34 Cells ◽  
Cd56 Expression ◽  
Acute Myeloid

Abstract Abstract 4908 Immunophenotyping Features in Acute Myeloid Leukemia (AML) with NPM1 and/or FLT-3 Positive Pervin Topçuoglu, Klara Dalva, Sinem Civriz Bozdag, Önder Arslan, Muhit Özcan, Osman Ýlhan, Hamdi Akan, Meral Beksaç, Günhan Gürman Aim: We aimed to evaluate immunophenotypical (IP) features in AML pts with NPM1+ and/or FLT3+ except on acute promyelocytic leukemia. Patients&Method: Between Nov 2009 and Feb 2011, we retrospectively analyzed IP features by flow cytometry (FCM) in 51 pts (46M;17F) with new diagnosed AML. Median age was 46 years (range: 14–71 ys). The mutations of NMP1 and FLT-3 TKD&ITD were determined by the methods of RQ-PCR or RFLP, respectively in the samples of bone marrow (n=31) or periheral blood (n=20) at the diagnosis. Antigenic expression of leukemic cells was analyzed by four-color FCM (FITC, PE, PerCP&APC) based by Nomdedeu et al researh (Leuk res 2011; 35:163) (Table-1). Results: We detected NMP1+ mutation in 16 patients. Of these, three were associated with mutations of FLT3-ITD (n=2) or -TKD (n=1). Twelve patients had FLT3+ (9 ITD or 3 TKD). More than half of the patients without any mutation were CD15+/CD34+/HLA-DR+ and 11.5% for CD34 negative. Similarly, the patients with FLT-3 positive were mostly CD34+ as the pts w/o any mutations. Contrary, most of the pts with NMP1+ were CD34 negative (56.3%) (Table 1). When evaluated the complete IP in leukemic cells, the expression of CD123 was significantly marked in the patients with NPM1+ and/or FLT3+ than those w/o mutations (p=0.008). While the co-expression of CD7 and CD117 was found in 67% of the pts w/o any mutations, 30% of the pts with NMP1 and/or FLT-3 ITD (p=0.01). CD56 expression was detected in more pts with NMP1+ than those with FLT-3+ (40% vs 8%, p=0.04). Besides, CD36 expression was positive in the all pts with FLT3-ITD than TKD+ (p=0.005). More intensive CD33 expression was seen in NMP1+ pts. The expression of CD64 was similar in all three mutations. Conclusion: Though NMP1 mutation was associated more CD34+ cells, more FLT3+ pts had CD34 positivity. The expression of CD123 was especially associated with the mutations. Aberrant expression of CD56 was in more pts with NPM1+, but CD36 for FLT3-ITD. These data might be a step for a study aiming to show a correlation between the type of mutations combined with IP features of leukemic cells and clinical characteristics or disease course of AML pts. Disclosures: No relevant conflicts of interest to declare.

Outcome Of Patients With Acute Myeloid Leukemia/High Risk MDS According To The Kidney Function

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5007-5007
Author(s):  
Ahmed Malkawi ◽  
Ankit Anand ◽  
Ali Al-Ameri ◽  
Mohamed Abdelfatah ◽  
Zeyad Kanaan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Survival Analysis ◽  
Glomerular Filtration Rate ◽  
High Risk ◽  
Glomerular Filtration ◽  
Myeloid Leukemia ◽  
Filtration Rate ◽  
Myelogenous Leukemia ◽  
Number Of Patients ◽  
Acute Myeloid

Abstract Background Acute renal failure or injury is a common complication of treatment of patients with acute myelogenous leukemia (AML) or high risk MDS, but the effect of renal function of patients who have acute myeloid leukemia/high risk MDS is not clearly highlighted as a predictor of survival, to the best of our knowledge this issue has not been studied in depth before. Aim study the effect of chronic kidney disease on the survival of patient with acute myeloid leukemia/High Risk MDS. Methods A retrospective study of all AML & high risk MDS patients treated at AGMC, Ohio, USA during 2001-2010. After IRB approval of the project, patients’ charts were reviewed to gather information on demographics, diagnosis types/subtypes, glomerular filtration rate (GFR), treatment, and cytogenetics. Patients were classified as low-intermediate risk or high risk according to cytogenetic background using WHO criteria. Also according to GFR patients were classified to GFR <30, 30 - 60 and > 60. Overall survival (OS) rates were determined by Kaplan-Meier Survival Analysis. Prognostic factors were evaluated by Log Rank analysis. Result Out of 130 patients we were able to classify 99 patients (75%). Patient were grouped into 59 Pts with GFR>60, 37 Pts with GFR 30-60 and 3 Pts with GFR<30. Time to event survival analysis was done. Conclusion Glomerular filtration rate GFR is a major identified factor in patients survival who have acute myeloid leukemia AML/High Risk MDS, those patients with GFR 30-60 do better in term of survival, we don’t have any explanation for that, more data with high number of patients needed to elaborate on this issue. Disclosures: No relevant conflicts of interest to declare.

Measurement of HSP90 and HSP70 in CD34-Positive Cells: Lower Levels in Myelodysplastic Syndrome Than in Acute Myeloid Leukemia and Correlation with Clinical Behavior.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3426-3426
Author(s):  
M. Gorre ◽  
I. Jilani ◽  
R. Chang ◽  
H. Chan ◽  
R. Urcia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Binding Capacity ◽  
Rational Approach ◽  
Specific Cell ◽  
Cd34 Cells ◽  
Shock Proteins ◽  
Acute Myeloid

Abstract Heat shock proteins (HSPs) are molecular chaperones involved in binding and regulating the levels of several client cellular proteins. HSPs are induced by stress and play a role in the modulation of apoptosis and proliferation. Expression of HSPs by acute myeloid leukemia (AML) cells has been reported to correlate with more aggressive disease. Here we used a flow cytometry approach to quantify the expression of HSP90 and HSP70 in specific cell populations in bone marrow. Quantification using QuantiBRITE and PE (phycoerythrin)-labeled antibodies with a 1:1 ratio allowed us to specifically measure the antibody binding capacity in 100 CD34+ cells (molecules/100 CD34+ or CD3+ cells). Using this approach, we compared bone marrow samples from patients with myelodysplastic syndrome (MDS) and patients with AML. This approach can also be used to monitor patients treated with therapeutic agents that target HSPs, such as 17-allylamino-17-demethoxygeldamycin (17AAG). The percentage of CD34+ cells expressing HSP90 (P=0.008) and HSP70 (P&lt;0.001) was significantly lower in MDS (n=20) than in AML (n=33) patients. Similarly, the percentage of CD3+ cells expressing HSP90 and HSP70 was significantly higher in MDS than in AML patients (P&lt;0.01). This suggests that the environment in the bone marrow (cytokines, chemokines, other factors) may affect the levels of HSPs in neoplastic and normal cells in a similar fashion. In patients with MDS, higher levels of HSP90 were associated with shorter survival (P=0.03). However, after achieving remission (CR), MDS patients who expressed high levels of HSP90 had significantly longer remission duration (CRD) (P=0.03). These findings not only confirm that the environment and blasts in patients with MDS are different from those in patients with AML, but also suggest that therapy targeting HSPs may be a rational approach in patients with MDS. Figure Figure

MicroRNA Signatures Associated with Cytogenetics and Outcome in Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 151-151
Author(s):  
Ramiro Garzon ◽  
Stefano Volinia ◽  
Chang G. Liu ◽  
Flavia Pichiorri ◽  
Tiziana Palumbo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Treatment Response ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Cytogenetic Abnormalities ◽  
Resistant Disease ◽  
Cd34 Cells ◽  
Differentiation Stage ◽  
Acute Myeloid

Abstract MicroRNAs are small non-coding RNAs of 19–25 nucleotides in length that are negative regulators of gene expression. Findings over the last few years indicate that microRNAs are involved in fundamental cellular process, including development and hematopoietic differentiation. Acute myeloid leukemia (AML) is a heterogeneous disorder that is characterized by proliferation of immature cells. Although there are well defined molecular subtypes of AML, the pathogenesis in the majority of cases is largely unknown. Focusing on known genes will not likely suffice to uncover the nature of the AML. The integration of a whole genome approach including non-coding RNA gene products may lead to an improve understanding of the biology of AML. Methods: To determine whether microRNAs are associated with known cytogenetic abnormalities and biological features in AML, we evaluated the microRNA expression profiles of 176 samples of adult AML with intermediate and poor risk cytogenetics and 10 CD34+ cells from healthy donors using a microarrays platform. After normalization, data were analyzed using significance analysis of microarrays and prediction analysis of microarrays software. An independent set of 28 patients with AML was used to validate the signatures using quantitative real time PCR. Treatment response was evaluated in 29 newly AML diagnosed patients 4 to 6 weeks after induction chemotherapy with idarubicin and cytarabine by bone marrow examination. Complete remission was defined as less than 5% blasts in the bone marrow. Otherwise it was categorized as resistant disease. Results: We found several microRNAs differentially expressed between CD34+ cells and all the AML samples. A subset of these microRNAs reflects the differentiation stage of the leukemias and correlate with the French-American-British classification of AML. Likewise, microRNAs are closely associated with the prevalent cytogenetic abnormalities. A common signature including the over expressed miR-20; miR-17, miR-25 and miR-191 are associated with short overall survival, while miR-29b is found down-regulated in patients with resistant disease. Furthermore, we proved experimentally that miR-29b regulates negatively MCL-1, a critical apoptosis regulator, which has been found up-regulated and associated with relapse and chemotherapy resistance in leukemia. Conclusions: MicroRNAs expression in AML is closely associated with differentiation stage, morphology and cytogenetics. A subset of MicroRNAs is correlated with survival and treatment response.

scholarly journals Efficacy and Safety of Decitabine Combined with IA Regimen in the Treatment of Newly Diagnosed Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2341-2341
Author(s):  
Lifen Kuang ◽  
Juan Li
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
High Risk Group ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Acute Myeloid

Abstract Objective: To evaluate the efficacy and safety of decitabine combined with IA regimen in the treatment of newly diagnosed acute myeloid leukemia. Methods: From September 1, 2013 to October 18, 2019, 164 newly diagnosed acute myeloid leukemia patients who received IA or decitabine combined with IA induction chemotherapy who were hospitalized in the Department of Hematology of the First Affiliated Hospital of Sun Yat-sen University were enrolled. The efficacy and side effects of treatment were analyzed. Results: The complete remission rate of decitabine combined with IA regimen chemotherapy group (n=88) and IA regimen chemotherapy group (n=76) was 83.0% vs. 68.4% (P=0.029, Fig 1). Subgroup analysis (table 1) showed that age ≥40 years old, WBC＜10*10^9/L, Hb＞85g/L, PLT≥50*10^9/L, MCV≥98fL, ratio of bone marrow immature cells ≤45%, NCCN intermediate-risk or high-risk group, patients with FLT3ITD mutation had a higher CR rate in the decitabine combined with IA regimen group. Multivariate analysis showed that combined decitabine was an independent favorable factor affecting the CR rate (OR 3.559, 95% CI: 1.554-8.151, P=0.003). Compared with the IA group, patients in the decitabine combined with IA group took longer to rebuild the granule system (20 days vs 19 days, P=0.026), and the incidence of infection was higher (93.2% vs 78.8%, P=0.028) (table 2). Conclusion: Compared with the IA regimen, the decitabine combined with the IA regimen significantly improves the induction chemotherapy response rate of newly diagnosed non-M3 AML patients, especially for patients with the following characteristics: age ≥ 40 years old, WBC &lt;10*10^ 9/L, Hb＞85g/L, PLT≥50*10^9/L, MCV≥98fL, bone marrow immature cell proportion ≤45%, NCCN risk stratification medium-risk or high-risk group, FLT3ITD mutation. After combining with decitabine, the patient's granular bone marrow suppression increased. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

MN1 Expression Predicts Prognosis of Acute Myeloid Leukemia with Normal Cytogenetics.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2351-2351
Author(s):  
Michael Heuser ◽  
Gernot Beutel ◽  
Jürgen Krauter ◽  
Nils von Neuhoff ◽  
Brigitte Schlegelberger ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Performance Status ◽  
Ecog Performance Status ◽  
Free Survival ◽  
Cd34 Cells ◽  
Significant Difference ◽  
Normal Cytogenetics ◽  
Acute Myeloid

Abstract Cytogenetic aberrations are important prognostic factors in acute myeloid leukemia (AML). However, approximately half of adult AML patients lack cytogenetic abnormalities and identification of predictive molecular markers might improve therapy. Fusion of meningioma-1 (MN1) to TEL (ETV6) has been found in AML and MDS with t(12;22)(p13;q11). However, expression levels of MN1 have not been reported previously in AML. We evaluated MN1 expression as a prognostic marker in 142 AML patients aged 18–60 years with normal cytogenetics, who were uniformely treated according to the AML-SHG 1/99 trial. Patients received intensive, cytarabine-based induction and consolidation treatment including allogeneic progenitor cell transplantation if an HLA-compatible sibling was available, or in case of relapse. Specimens were obtained at diagnosis, and routine cytogenetic, FLT3-mutation, and MLL-PTD analyses were performed. MN1 expression was quantified by real-time RT-PCR on a LightCycler using QuantiTect SYBR Green. AML samples were dichotomized at the median value resulting in two groups: a low MN1 group and a high MN1 group. Baseline characteristics and outcome parameters were compared between these two groups. In addition, CD34+ cells were immunomagnetically enriched from mobilized blood of a healthy donor using MACS CD34 isolation kit. Cells were cultured in IMDM medium with various cytokines including either G-CSF, M-CSF or EPO. At various time points, cells were harvested and analyzed for MN1 expression. There were no significant differences between low MN1 and high MN1 expressing patients with respect to age, gender, ECOG performance status, diagnosis of de novo or secondary AML, FAB morphology, white blood cell count, percentage of blasts in blood or bone marrow, FLT3 mutations, or MLL-PTD. Low MN1 expressing patients significantly more often achieved a good response to the first course of induction treatment defined as blasts in bone marrow below 5%, no blasts in peripheral blood, and no extramedullary manifestation at day 15 compared to high MN1 expressing patients (87.3% vs. 71.8%, p=.02). There was no significant difference for remission status between the two groups. High MN1 expression predicted significantly shorter event-free survival (19% vs. 45.8% at 3 years, log-rank p=.0009), shorter relapse-free survival (23% vs. 52.8% at 3 years, log-rank p=.001), and shorter overall survival (38.2% vs. 58.8% at 3-years, log-rank p=.03). The high MN1 group relapsed significantly more often compared to the low MN1 group (56.7% vs. 35%, p=.02), and thus received an allogeneic transplant significantly more often (50.7% vs. 33.8%, p=.04). In multivariate analysis including known risk factors only MN1 expression, age (above the median compared to below the median age), and ECOG performance status (0 or 1 compared to 2) remained significant (hazard ratio: 2 (p=.01), 2.1 (p=.005) and 2.8 (p=.005), respectively). MN1 expression in CD34+ cells was 37-fold higher compared to the CD34− cell fraction. However, by in vitro differentiation of CD34+ cells using various cytokines including either G-CSF, M-CSF or EPO, MN1 expression dropped to levels found in the CD34− fraction within 7 days of culture. In conclusion, high MN1 expression predicts adverse prognosis and may define an important risk factor in AML with normal cytogenetics. Its upregulation in hematopoietic progenitor cells hints at a functional role of MN1 in blocking differentiation.

In Acute Myeloid Leukemia Both Malignant and Normal Stem Cells Can Be Detected in Remission Bone Marrow.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2537-2537 ◽  
Author(s):  
Anna van Rhenen ◽  
Nicole Feller ◽  
Angele Kelder ◽  
Bijan Moshaver ◽  
Sonja Zweegman ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Risk Stratification ◽  
Therapeutic Intervention ◽  
Myeloid Leukemia ◽  
Fish Analysis ◽  
Patient Risk ◽  
Acute Myeloid

Abstract In CD34-positive acute myeloid leukemia (AML), the leukemia-initiating event is thought to occur in the CD34+CD38− stem cell compartment. Survival of these cells after chemotherapy hypothetically results in minimal residual disease (MRD) and leads to relapse. C-type lectin-like molecule 1 (CLL-1) could serve as a possible target for therapy, as we previously showed that it is expressed on malignant CD34+CD38− cells at diagnosis and not on normal CD34+CD38− cells (van Rhenen et al., Blood106: 6a, 2005). CLL-1 expression is also present on malignant CD34+CD38− cells after chemotherapy. In the present study we investigated whether other antigens are also aberrantly expressed on CD34+CD38− cells in AML patients at diagnosis which would allow detection of AML CD34+CD38− cells in remission bone marrow. Such would offer opportunities for patient risk stratification and guidance of therapeutic intervention. Flowcytometry was performed on bone marrow CD34+CD38− cells in AML at diagnosis, after chemotherapy and in normal (NBM) and regenerating (RBM) bone marrow. Antibodies were anti-CD34, anti-CD45 and anti-CD38 together with antibodies against CLL-1, CD2, CD5, CD7, CD11b, CD19 and CD56, apart from CLL-1 all used as leukemia-associated phenotypes (LAPs) in immunophenotypic MRD detection (Feller et al., Leukemia8:1380, 2004; further referred to as “whole blast” MRD). In diagnosis AML marker expression on CD34+CD38- cells was scored as <50% or >50%, because at least 50% expression is needed for accurate measurements of malignant CD34+CD38- cells after chemotherapy. At diagnosis, 60/77 AML samples were CD34-positive. A reliable number of CD34+CD38- events (>20) could be measured in 56/60 cases. CLL-1 expression >50% was observed in 15/60 cases, LAP expression in 9/60 cases and both CLL-1 and LAP in 8/60 cases. Altogether, in 32/60 CD34-positive cases, detection of malignant CD34+CD38- cells was possible. In NBM (n=4) as well as in RBM, the CD34+CD38- cells did show low CLL-1 (n=6) and low LAP (n=2, for all antigens) expression (all <3%). For three AML samples in which a leukemia-specific translocation was present, FISH analysis showed the translocation in CD34+CD38-LAP+ cells. Therefore, CLL-1 and/or LAP staining might enable to accurately discriminate between residual normal and malignant CD34+CD38- cells after chemotherapy. Firstly, we found that irrespective of the aberrant phenotype or the time point of analysis the frequency of residual malignant CD34+CD38- cells significantly correlated with “whole blast” MRD (r=0.42, p=0.008, n=38). Secondly the ratio between malignant and normal CD34+CD38- cells (stem cell ratio) was found to parallel both CD34+CD38- cell frequency and “whole blast” MRD. Both parameters, similar to “whole blast” MRD, parallelled clinical outcome with decreases when entering remission, no changes in non-responders and increases with forthcoming relapses. In 3/60 cases in which “whole blast” MRD could not be used, stem cell MRD could be performed. Since the populations are so well defined [CD34+/CD38−/CD45dim/aberrant marker] stem cell MRD will require less extensive experience than currently used MRD frequency assessment. These advantages are expected to increase as the use of 5 or more fluorescence channels will improve the success of stem cell MRD. In conclusion it is possible to detect malignant stem cells in AML patients at diagnosis and after chemotherapy, which would offer opportunities for future patient risk stratification and guidance of therapeutic intervention.

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