scholarly journals Cell‐based and antibody‐mediated immunotherapies directed against leukemic stem cells in acute myeloid leukemia: Perspectives and open issues

2020 ◽  
Author(s):  
Peter Valent ◽  
Karin Bauer ◽  
Irina Sadovnik ◽  
Dubravka Smiljkovic ◽  
Daniel Ivanov ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemic Stem Cells ◽  
Acute Myeloid ◽  
Open Issues

NUP98-PHF23 fusion is recurrent in acute myeloid leukemia and shares gene expression signature of leukemic stem cells

2016 ◽  
Vol 45 ◽  
pp. 1-7 ◽  
Author(s):  
Hao Ho ◽  
Alyza M. Skaist ◽  
Aparna Pallavajjala ◽  
Raluca Yonescu ◽  
Denise Batista ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Expression Signature ◽  
Leukemic Stem Cells ◽  
Expression Signature ◽  
Acute Myeloid

The Target Receptor Siglec-3 (CD33) Is Expressed on AML Stem Cells in a Majority of All Patients with AML.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4324-4324
Author(s):  
Alexander W. Hauswirth ◽  
Stefan FLorian ◽  
Maria-Theresa Krauth ◽  
Gerit-Holger Schernthaner ◽  
Edgar Selzer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Staining Technique ◽  
Scid Mice ◽  
Leukemic Cells ◽  
Cytostatic Drug ◽  
Leukemic Stem Cells ◽  
Targeting Therapy ◽  
Acute Myeloid

Abstract The cell surface antigen Siglec-3 = CD33 is becoming increasingly important as target of therapy in acute myeloid leukemia (AML). In particular, a conjugate consisting of the humanized CD33 antibody P67.6 (gemtuzumab) and the cytostatic drug calicheamicin has been developed for clinical use and was found to work as an effective antileukemic agent (Mylotarg®) in patients with CD33+ AML. In normal myelopoiesis, expression of CD33 is restricted to advanced stages of differentiation, whereas primitive stem cells do not express CD33 (Siglec-3). In line with this notion, CD33-targeting therapy is a non-myeloablative approach. In the present study, we asked whether leukemic stem cells in patients with AML express CD33. For this purpose, a multicolor-staining technique was applied in eleven patients with AML. Leukemic stem cells were defined as CD34+/CD38−/CD123+ cells. In all patients in whom the majority of myeloblasts expressed CD33 (=CD33+ AML, n=8), the AML progenitor cells reacted with the CD33 antibody P67.6. Repopulation experiments utilizing NOD/SCID mice confirmed that the AML stem cells in these patients reside within the CD33+ subpopulation of leukemic cells. Moreover, AML stem cells (CD34+/CD38−/CD123+ cells) highly purified (>98% purity) from patients with (CD33+) AML by cell sorting, were found to express CD33 mRNA in RT-PCR analyses. To demonstrate that AML stem cells can also reside within the CD33-negative fraction of the AML clone, we purified CD33-negative cells in a patient with AML in whom a majority of leukemic stem cells were found to lack CD33. In this particular patient, the CD33-negative cells were found to repopulate NOD/SCID mice with leukemias in the same way as the entire leukemic clone did. The CD33 antigen was neither detectable on CD34+/CD38− cells in the normal bone marrow nor on leukemic stem cells in patients with CD33-negative AML. In summary, our data show that leukemic stem cells in patients with CD33+ AML frequently express the target receptor CD33. This observation is in favor of novel treatment concepts employing CD33-targeting antibodies (Mylotarg®) in acute myeloid leukemia.

Gfi1b-A Novel Tumor Suppressor In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3795-3795
Author(s):  
Lacramioara Botezatu ◽  
Judith Hönes ◽  
Amos Zeller ◽  
Lars C. Michel ◽  
Andre Görgens ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Transcription Factors ◽  
Tumor Suppressor ◽  
Myeloid Leukemia ◽  
Leukemic Stem Cells ◽  
Hematopoietic Stem ◽  
Blast Cells ◽  
Leukemia Development ◽  
Acute Myeloid

Abstract The proper differentiation of hematopoietic stem cells is regulated by a concert of different so called transcription factors. Growth Factor Independence 1b (Gfi1b) is a repressing transcription factor, which is pivotal for the proper emergence and maturation of erythrocytes and platelets. Furthermore, Gfi1b controls quiescence as well as cell cycle progression of hematopoietic stem cells and early progenitor cells. It has been shown for other transcription factors that a disturbed function of these transcription factors can be the basis of malignant diseases such acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). MDS is characterized by disturbed differentiation of one or several hematopoietic lineages. The accumulation of malignant blast cells, which are arrested in their development, is a key feature of AML. Since transcription factors play a role in AML development, we sought to investigate whether Gfi1b might also play a role in the development and progression of AML. Based on published gene expression arrays and own patient samples, we observed that Gfi1b is expressed at a lower level in leukemic blasts and leukemic stem cells compared to the non-malignant control cells. We correlated Gfi1b expression level in blast cells of patients from Essen and we found out that patients with high Gfi1b levels had a poor prognosis and an increased risk of relapse. In contrast low levels of Gfi1b expression were associated with a good prognosis. To test how different levels of Gfi1b might influence initiation of AML we have mouse strains available expressing Gfi1b at different expression levels. We have Gfi1b wt mice with one allele of Gfi1b deleted (Gfi1b het) and Gfi1b conditional mice, in which the expression of Gf1b (Mx Cre tg Gfi1b fl/fl) can be abrogated after injecting these mice with pIpC. To explore the role of Gfi1b in leukemia development, we used different murine AML models, resembling human leukemia. First these mice were crossed with Nup98HoxD13 transgenic mice, a mouse strain that develops a disease similar to the human MDS. We observed that Gfi1b heterozygosity (n=15) accelerated AML development (p=0,03) compared to wt mice (n=16). More importantly, complete absence of Gfi1b (n=8) results in a substantially earlier onset of AML, with a median survival time of about 50 days (p=0.002). To confirm our findings, we used a different murine AML model. Recurrent so called oncofusion proteins such as AML1-Eto9a, CBFbeta-Myh11 or MLL-AF9 are characteristic for certain subtypes of AML. We transduced Lineage negative (Lin-) bone marrow cells from wt, Gfi1b heterozygous (Gfi1b het) and Gfi1b deficient (MxCre Gfi1b fl/fl) mice with retroviruses encoding either AML1-Eto9a or MLL-AF9 oncofusion -proteins. Transduced Gfi1b heterozygous or Gfi1b deficient cells generated more colonies and higher cell number than wt transduced cells. We also used mice transgenically expressing CBFbeta-Myh11. Deletion of Gfi1b accelerated leukemia formation in these mice compared to mice in which Gfi1b was still expressed. On a molecular level, we found that loss of Gfi1b leads to increased levels of ROS level. It has been shown by other groups, that increased levels of Gfi1b contribute to leukemia development. In addition, Gfi1b represses the expression of Integrin beta 3 (ITGB3). Absence of Gfi1b leads to higher expression level of ITGB3. ITGB3 has been shown to promote growth and expansion of leukemic stem cells, which play an important role in AML development. Thus we report here that Gfi1b acts as a novel tumor suppressor in AML development. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document