scholarly journals Location First: Targeting Acute Myeloid Leukemia Within Its Niche

2020 ◽  
Vol 9 (5) ◽  
pp. 1513 ◽  
Author(s):  
Alice Pievani ◽  
Marta Biondi ◽  
Chiara Tomasoni ◽  
Andrea Biondi ◽  
Marta Serafini
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Patient Specific ◽  
Human Leukemia ◽  
Bm Niche ◽  
Poor Outcomes ◽  
New Treatments ◽  
Acute Myeloid

Despite extensive research and development of new treatments, acute myeloid leukemia (AML)-backbone therapy has remained essentially unchanged over the last decades and is frequently associated with poor outcomes. Eradicating the leukemic stem cells (LSCs) is the ultimate challenge in the treatment of AML. Emerging evidence suggests that AML remodels the bone marrow (BM) niche into a leukemia-permissive microenvironment while suppressing normal hematopoiesis. The mechanism of stromal-mediated protection of leukemic cells in the BM is complex and involves many adhesion molecules, chemokines, and cytokines. Targeting these factors may represent a valuable approach to complement existing therapies and overcome microenvironment-mediated drug resistance. Some strategies for dislodging LSCs and leukemic blasts from their protective niche have already been tested in patients and are in different phases of the process of clinical development. Other strategies, such as targeting the stromal cells remodeling processes, remain at pre-clinical stages. Development of humanized xenograft mouse models, which overcome the mismatch between human leukemia cells and the mouse BM niche, is required to generate physiologically relevant, patient-specific human niches in mice that can be used to unravel the role of human AML microenvironment and to carry out preclinical studies for the development of new targeted therapies.

scholarly journals Occurrence of Acute Myeloid Leukemia in Young Pregnant Women

2008 ◽  
Vol 1 ◽  
pp. CMBD.S823
Author(s):  
Juliane Menezes ◽  
Mariana Emerenciano ◽  
Flávia Pimenta ◽  
Gilson Guedes Filho ◽  
Isis Q. Magalhães ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Young Women ◽  
Acute Leukaemia ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Fusion Genes ◽  
Life Threatening ◽  
Poor Outcomes ◽  
Acute Myeloid ◽  
In Pregnancy

Although acute leukaemia is rare in pregnancy its importance lies in its life-threatening potential, both to the child and the mother. The possibility of vertical transmission of leukemic cells increases the attention devoted to these patients and their offspring. Three cases of pregnant young women (15-17 years of age) with AML are presented. This series of cases is the first report where gene abnormalities such as ITD mutations of the FLT3 gene and AML1/ETO fusion genes were screened in pregnant AML patients and their babies, so far. Unfortunately, very poor outcomes have been associated to similar cases described in literature, and the same was true to the patients described herein. Although very speculative, we think that the timing and possible similar exposures would be involved in all cases.

scholarly journals Role of Genetic Analysis in New Treatments of Acute Myeloid Leukemia

2018 ◽  
Author(s):  
Mehrdad Payandeh ◽  
Masoud Sadeghi ◽  
Edris Sadeghi ◽  
Mehrnoush Aeinfar
Keyword(s):  
Acute Myeloid Leukemia ◽  
Genetic Analysis ◽  
Myeloid Leukemia ◽  
New Treatments ◽  
Acute Myeloid

Collaboration of the Meningioma 1 (MN1) Oncogene with MLL-Fusions in Pediatric Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3786-3786
Author(s):  
Ting Liu ◽  
Dragana Jankovic ◽  
Laurent Brault ◽  
Sabine Ehret ◽  
Vincenzo Rossi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Leukemic Cells ◽  
Human Leukemia ◽  
Fusion Genes ◽  
Pediatric Leukemia ◽  
Acute Myeloid

Abstract Expression of meningioma 1 (MN1) has been proposed to be a negative prognostic marker in adult acute myeloid leukemia (AML). In pediatric leukemia, we found overexpression of MN1 in 53 of 88 cases: whereas no MN1 expression was detected in T-cell acute lymphoblastic leukemia (T-ALL), significant amounts of MN1 were found in immature B-cell ALL and most cases of infant leukemia. Interestingly, 17 of 19 cases harboring fusion genes involving the mixed-lineage leukemia (MLL-X) gene showed elevated MN1 expression. Lentiviral siRNA mediated MN1 knock-down resulted in cell cycle arrest and impaired clonogenic growth of 3 MLL-X-positive human leukemia cell lines overexpressing MN1 (THP-1, RS4;11, MOLM-13). In a mouse model of MLL-ENL-induced leukemia we found MN1 to be overexpressed as a consequence of provirus integration. Strikingly co-expression of MN1 with MLL-ENL resulted in significantly reduced latency for induction of an AML phenotype in mice suggesting functional cooperation. Immunophenotyping and secondary transplant experiments suggested that MN1 overexpression seems to expand the L-GMP cell population targeted by the MLL-ENL fusion. Gene expression profiling allowed defining a number of potential MN1 hematopoietic targets. Upregulation of CD34, FLT3, HLF, or DLK1 was validated in bone marrow transiently overexpressing MN1, in MN1-induced mouse acute myeloid leukemia, as well as in pediatric leukemias with elevated MN1 levels. Our work shows that MN1 is overexpressed in a significant fraction of pediatric acute leukemia, is essential for growth of leukemic cells, and that MN1 can act as a cooperating oncogene with MLL-ENL most probably through modification of a distinct gene expression program that leads to expansion of a leukemic progenitor population targeted by MLL-fusion genes.

scholarly journals Critical Role of Lama4 for Hematopoiesis Regeneration and Acute Myeloid Leukemia Progression

Blood ◽  
2021 ◽  
Author(s):  
Huan Cai ◽  
Makoto Kondo ◽  
Lakshmi Sandhow ◽  
Pingnan Xiao ◽  
Anne-Sofie Johansson ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Proliferation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Critical Role ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Bm Niche ◽  
Acute Myeloid

Impairement of normal hmatopoiesis and leukemia progression are two well-linked processes during leukemia development and controlled by the bone marrow (BM) niche. Extracellular matrix proteins including laminin are important BM niche components. However, their role in hematopoiesis regeneration and leukemia is unknown. Laminin α4 (Lama4), a major receptor-binding chain of several laminins, is altered in BM niches in mice with acute myeloid leukemia (AML). So far, the impact of Lama4 on leukemia progression remains unknown. We here report that Lama4 deletion in mice resulted in impaired hematopoiesis regeneration following irradiation-induced stress, which is accompanied with altered BM niche composition and inflammation. Importantly, in a transplantation-induced MLL-AF9 AML mouse model, we demonstrate accelerated AML progression and relapse in Lama4-/-mice. Upon AML exposure, Lama4-/- mesenchymal stem cells (MSCs) exhibited dramatic molecular alterations including upregulation of inflammatory cytokines that favor AML growth. Lama4-/- MSCs displayed increased anti-oxidant activities and promoted AML stem cell proliferation and chemoresistance to cytarabine, which was accompanied by increased mitochondrial transfer from the MSCs to AML cells and reduced reactive oxygen species in AML cells in vitro. Similarly, we detected lower levels of reactive oxygen species in AML cells from Lama4-/- mice post-cytarabine treatment. Notably, LAMA4 inhibition or knockdown in human MSCs promoted human AML cell proliferation and chemoprotection. Together, our study for the first time demonstrates a critical role of Lama4 in impeding AML progression and chemoresistance. Targeting Lama4 signaling pathways may offer potential new therapeutic options for AML.

scholarly journals Clinical Implications of Inflammation in Acute Myeloid Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Christian Récher
Keyword(s):  
Acute Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Leukemic Cells ◽  
Prognostic Impact ◽  
Acute Myeloid

Recent advances in the description of the tumor microenvironment of acute myeloid leukemia, including the comprehensive analysis of the leukemic stem cell niche and clonal evolution, indicate that inflammation may play a major role in many aspects of acute myeloid leukemia (AML) such as disease progression, chemoresistance, and myelosuppression. Studies on the mechanisms of resistance to chemotherapy or tyrosine kinase inhibitors along with high-throughput drug screening have underpinned the potential role of glucocorticoids in this disease classically described as steroid-resistant in contrast to acute lymphoblastic leukemia. Moreover, some mutated oncogenes such as RUNX1, NPM1, or SRSF2 transcriptionally modulate cell state in a manner that primes leukemic cells for glucocorticoid sensitivity. In clinical practice, inflammatory markers such as serum ferritin or IL-6 have a strong prognostic impact and may directly affect disease progression, whereas interesting preliminary data suggested that dexamethasone may improve the outcome for AML patients with a high white blood cell count, which paves the way to develop prospective clinical trials that evaluate the role of glucocorticoids in AML.

scholarly journals Childhood acute myeloid leukemia in mice with severe combined immunodeficiency

Blood ◽  
1994 ◽  
Vol 84 (1) ◽  
pp. 20-26
Author(s):  
LM Chelstrom ◽  
R Gunther ◽  
J Simon ◽  
SC Raimondi ◽  
R Krance ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Scid Mouse ◽  
Severe Combined Immunodeficiency ◽  
Scid Mice ◽  
Leukemic Cells ◽  
Human Leukemia ◽  
Combined Immunodeficiency ◽  
Kidney Capsule ◽  
Acute Myeloid

Primary bone marrow blasts from 4 children with t(8;21) acute myeloid leukemia (AML), 6 children with inv(16) AML, and 2 children with t(9;11) AML were injected intravenously or transplanted under the kidney capsule of sublethally irradiated mice with severe combined immunodeficiency (SCID). Leukemic cells from all AML patients infiltrated the SCID mouse thymus, suggesting that the thymic microenvironment supports the survival and growth of human AML blasts. Blasts from 1 of 4 t(8;21) AML patients and 4 of 6 inv(16) AML patients caused histopathologically detectable disseminated leukemia. Blasts from the remaining patients produced disseminated occult leukemia that was only detected by polymerase chain reaction. Occurrence of histopathologically detectable disseminated leukemia was dependent on intravenous injection of leukemic cells; none of the mice challenged with an inoculum transplanted under the kidney capsule developed overt leukemia. No obvious association was noted between occurrence of leukemia in SCID mice and clinical or laboratory features presented by patients, including age, sex, or leukocyte count at diagnosis. To our knowledge, this study is the first to show that leukemic blasts from children with newly diagnosed AML, especially inv(16) AML, can cause disseminated human leukemia in SCID mice without exogenous cytokine support. The SCID mouse model system may prove particularly useful for designing more effective treatment strategies against childhood AML.

scholarly journals Expression of isoforms of the human receptor tyrosine kinase c-kit in leukemic cell lines and acute myeloid leukemia

Blood ◽  
1993 ◽  
Vol 82 (4) ◽  
pp. 1151-1158 ◽  
Author(s):  
PS Crosier ◽  
ST Ricciardi ◽  
LR Hall ◽  
MR Vitas ◽  
SC Clark ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Cellular Transformation ◽  
Leukemic Cells ◽  
Leukemia Cell Line ◽  
Human Leukemia ◽  
Rnase Protection ◽  
Acute Myeloid

Abstract Because mutations in receptor tyrosine kinases may contribute to cellular transformation, studies were undertaken to examine c-kit in human leukemia. Isoforms of c-kit have been characterized in the human megakaryoblastic leukemia cell line M-07. Deletion of the four amino acids Gly-Asn-Asn-Lys in the extracellular domain represents an alternatively spliced isoform that has been shown by others, in mice, to be associated with constitutive receptor autophosphorylation (Reith et al, EMBO J 10:2451, 1991). Additional isoforms differ in the inclusion or exclusion of a serine residue in the interkinase domain, a region that contains the binding site for phosphatidylinositol 3- kinase. By RNase protection analysis, we have shown coexpression of the Gly-Asn-Asn-Lys+ and Gly-Asn-Asn-Lys- isoforms, with dominance of the Gly-Asn-Asn-Lys- transcript, in normal human bone marrow, normal melanocytes, a range of tumor cell lines, and the blasts of 23 patients with acute myeloid leukemia. Analysis of transcripts for the Ser+ and Ser- isoforms also showed coexpression in all normal and leukemic cells examined. The ratios of isoform expression for both the Gly-Asn-Asn-Lys and Ser variants were relatively constant, providing no evidence in the tumors examined that upregulation of one isoform contributes to the neoplastic process.

scholarly journals Fluorouracil selectively spares acute myeloid leukemia cells with long- term growth abilities in immunodeficient mice and in culture

Blood ◽  
1996 ◽  
Vol 88 (6) ◽  
pp. 1944-1950 ◽  
Author(s):  
W Terpstra ◽  
RE Ploemacher ◽  
A Prins ◽  
K van Lom ◽  
K Pouwels ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Severe Combined Immunodeficiency ◽  
Scid Mice ◽  
Leukemic Cells ◽  
Human Leukemia ◽  
Hematopoietic Stem ◽  
Acute Myeloid

A subset of leukemic cells is assumed to maintain long-term growth of acute myeloid leukemia (AML) in vivo. Characterization of these AML progenitor cells may further define growth properties of human leukemia. In vitro incubations with 5-fluorouracil (5-FU) have been used for enrichment of normal primitive hematopoietic stem cells. By analogy to normal hematopoiesis, it was hypothesized that primitive leukemic stem cells might be kinetically more inactive than colony- forming cells (colony-forming units-AML [CFU-AML]). To examine this hypothesis, conditions were established for incubation with 5-FU that eliminated all CFU-AML. These conditions selected a 5-FU-resistant AML fraction that was evaluated for its capacity for long-term growth by transplantation into mice with severe combined immunodeficiency (SCID) and long-term culture in the quantitative cobblestone area-forming cell (CAFC) assay. Transplantation of the 5-FU-resistant fraction of four cases of AML into SCID mice resulted in growth of AML. Whereas no CFU- AML survived, 31% to 82% of primitive (week-6) CAFC were recovered from the 5-FU-treated cells. Hematopoietic cells proliferating in the CAFC assay were shown to be leukemic by cytologic, cytogenetic, or molecular analysis. The reduction of AML growth as determined by outgrowth of AML in SCID mice was in the same order of magnitude as the primitive (week- 6) CAFC reduction. This indicates that both assays measure closely related cell populations and that the CAFC assay can be used to study long-term growth of AML. These results show a hierarchy of AML cells that includes 5-FU-resistant progenitors. These cells are characterized as primitive (week-6) CAFC and as leukemia-initiating cells in SCID mice.

scholarly journals Childhood acute myeloid leukemia in mice with severe combined immunodeficiency

Blood ◽  
1994 ◽  
Vol 84 (1) ◽  
pp. 20-26 ◽  
Author(s):  
LM Chelstrom ◽  
R Gunther ◽  
J Simon ◽  
SC Raimondi ◽  
R Krance ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Scid Mouse ◽  
Severe Combined Immunodeficiency ◽  
Scid Mice ◽  
Leukemic Cells ◽  
Human Leukemia ◽  
Combined Immunodeficiency ◽  
Kidney Capsule ◽  
Acute Myeloid

Abstract Primary bone marrow blasts from 4 children with t(8;21) acute myeloid leukemia (AML), 6 children with inv(16) AML, and 2 children with t(9;11) AML were injected intravenously or transplanted under the kidney capsule of sublethally irradiated mice with severe combined immunodeficiency (SCID). Leukemic cells from all AML patients infiltrated the SCID mouse thymus, suggesting that the thymic microenvironment supports the survival and growth of human AML blasts. Blasts from 1 of 4 t(8;21) AML patients and 4 of 6 inv(16) AML patients caused histopathologically detectable disseminated leukemia. Blasts from the remaining patients produced disseminated occult leukemia that was only detected by polymerase chain reaction. Occurrence of histopathologically detectable disseminated leukemia was dependent on intravenous injection of leukemic cells; none of the mice challenged with an inoculum transplanted under the kidney capsule developed overt leukemia. No obvious association was noted between occurrence of leukemia in SCID mice and clinical or laboratory features presented by patients, including age, sex, or leukocyte count at diagnosis. To our knowledge, this study is the first to show that leukemic blasts from children with newly diagnosed AML, especially inv(16) AML, can cause disseminated human leukemia in SCID mice without exogenous cytokine support. The SCID mouse model system may prove particularly useful for designing more effective treatment strategies against childhood AML.

scholarly journals DNAM-1/CD226 is functionally expressed on acute myeloid leukemia (AML) cells and is associated with favorable prognosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anna Chashchina ◽  
Melanie Märklin ◽  
Clemens Hinterleitner ◽  
Helmut R. Salih ◽  
Jonas S. Heitmann ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Allogenic Stem Cell Transplantation ◽  
Favorable Prognosis ◽  
Tnf Α ◽  
And Function ◽  
Prognostic Maker ◽  
Acute Myeloid

AbstractDNAM-1 is reportedly expressed on cytotoxic T and NK cells and, upon interaction with its ligands CD112 and CD155, plays an important role in tumor immunosurveillance. It has also been reported to be functionally expressed by myeloid cells, but expression and function on malignant cells of the myeloid lineage have not been studied so far. Here we analyzed expression of DNAM-1 in leukemic cells of acute myeloid leukemia (AML) patients. We found substantial levels of DNAM-1 to be expressed on leukemic blasts in 48 of 62 (> 75%) patients. Interaction of DNAM-1 with its ligands CD112 and CD155 induced release of the immunomodulatory cytokines IL-6, IL-8 IL-10 and TNF-α by AML cells and DNAM-1 expression correlated with a more differentiated phenotype. Multivariate analysis did not show any association of DNAM-1 positivity with established risk factors, but expression was significantly associated with clinical disease course: patients with high DNAM-1 surface levels had significantly longer progression-free and overall survival compared to DNAM-1low patients, independently whether patients had undergone allogenic stem cell transplantation or not. Together, our findings unravel a functional role of DNAM-1 in AML pathophysiology and identify DNAM-1 as a potential novel prognostic maker in AML.

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