Critical Role of c-Myc in Acute Myeloid Leukemia Involving Direct Regulation of miR-26a and Histone Methyltransferase EZH2

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.

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PRL2 Maintains Hematopoietic Stem and Progenitor Cells Through Regulating SCF/KIT Signaling

Blood ◽

10.1182/blood.v122.21.3674.3674 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3674-3674

Author(s):

Michihiro Kobayashi ◽

Yuanshu Dong ◽

Hao Yu ◽

Yunpeng Bai ◽

Sisi Chen ◽

...

Keyword(s):

Cell Proliferation ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Progenitor Cell ◽

Conflicts Of Interest ◽

Critical Role ◽

Hematopoietic Progenitor Cell ◽

Hematopoietic Stem ◽

Acute Myeloid

Abstract The phosphatase of regenerating liver family of phosphatases, consisting of PRL1, PRL2 and PRL3, represents an intriguing group of proteins implicated in cell proliferation and tumorigenesis. However, the role of PRLs in normal and malignant hematopoiesis is largely unknown. While SCF/KIT signaling plays an important role in hematopoietic stem and progenitor cell (HSPC) maintenance, how SCF/KIT signaling is regulated in HSPCs remains poorly understood. We here report that PRL2 regulates HSPC maintenance through regulating SCF/KIT signaling. To define the role of PRL2 in hematopoiesis, we analyzed the hematopoietic stem cell (HSC) behavior in Prl2 deficient mice generated by our group. Prl2 deficiency results in ineffective hematopoiesis and impairs the long-term repopulating ability of HSCs. In addition, Prl2 null HSPCs are less proliferative and show decreased colony formation in response to SCF stimulation. Furthermore, Prl2 null HSPCs show reduced activation of the PI3K/AKT and ERK signaling in steady state and following SCF stimulation. Importantly, we found that PRL2 associates with KIT and the ability of PRL2 to enhance SCF signaling depends on its enzymatic activity, demonstrating that PRL2 mediates SCF/KIT signaling in HSPCs. Thus, PRL2 plays a critical role in hematopoietic stem and progenitor cell maintenance through regulating SCF/KIT signaling. Furthermore, loss of Prl2 decreased the ability of oncogenic KITD814V mutant in promoting hematopoietic progenitor cell proliferation and in activation of signaling pathways. We also checked the expression of PRL2 proteins in human AML cell lines and found increased level of PRL2 proteins in some acute myeloid leukemia (AML) cells compared with normal human bone marrow cells, indicating that PRL2 may play a pathological role in AML. Our results suggest that the PRL2 phosphatase may be a druggable target in myeloproliferative disease (MPD) and acute myeloid leukemia (AML) with oncogenic KIT mutations. Disclosures: No relevant conflicts of interest to declare.

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Heterogeneity of Acute Myeloid Leukemia at the Stem Cell Level.

Blood ◽

10.1182/blood.v112.11.1355.1355 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1355-1355

Author(s):

Michael Heuser ◽

Laura Sly ◽

Courteney Lai ◽

Malina Leung ◽

Grace Lin ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Critical Role ◽

Normal Karyotype ◽

Complex Karyotype ◽

Gm Csf ◽

Limiting Dilution ◽

Acute Myeloid

Abstract Leukemias are considered hierarchically organized being maintained by a leukemia stem cell (LSC). Whereas LSCs become the primary focus for targeted therapies, little is known about the pathways regulating LSC fidelity. Using retroviral gene transfer of MN1, NUP98HOXD13 (ND13), or HOXA9 oncogenes and limiting-dilution transplantation we modelled leukemias with different LSC frequencies, and characterized critical signaling pathways by loss-of-function analysis. Here we establish the concept that LSCs are heterogeneous based on the number of activated transcriptional networks, and functionally characterize downstream targets that are critical for LSC activity. Constitutive expression of the very potent myeloid oncogene MN1 with the ND13 fusion gene in murine bone marrow cells results in acute myeloid leukemia (AML) that is phenotypically very similar to MN1-induced AML. However, limiting dilution analysis showed that the LSC frequency was 33 fold higher in MN1+ND13 cells compared to MN1 cells, and disease latency at the limiting dilution was significantly shorter in the combination model (p=.009). Whereas MN1-LSCs expanded 68-fold over a period of 6 days, MN1+ND13-LSCs expanded 131-fold more than MN1-LSCs as determined by the competitive repopulation unit (CRU) assay. To screen for functional differences of the two models we screened for differential cytokine responses in vitro. Interestingly, MN1+ND13 expressing cells proliferated in response to GM-CSF, whereas MN1 cells or ND13 cells did not. This was confirmed as well for MN1+HOXA9 expressing cells and their MN1+CTL or HOXA9+CTL expressing counterparts. We found that Stat1, Stat3, Stat5, and Erk1/2 were selectively phosphorylated upon cytokine stimulation in MN1+ND13 and MN1+HOXA9 cells compared to single-oncogene transduced cells. To test the role of Stat1 and Stat5b for LSC fidelity Stat1 −/− and Stat5b −/− cells were co-transduced with MN1 and HOXA9 and compared to wildtype cells in vitro and in vivo. Stat1 −/− cells transduced with MN1+HOXA9 proliferated slower than wildtype cells in response to GM-CSF but not with IL3/IL6/SCF. Proliferation of Stat5b −/− cells transduced with MN1+HOXA9 proliferated slower than wildtype cells in response to both GM-CSF and IL3/IL6/SCF (p<.05). CRU assays with MN1+HOXA9-transduced Stat1 −/− and Stat5b −/− cells demonstrated that the day 6 CRU was 6 and 77 fold reduced, respectively, compared to wildtype cells. As MN1 and HOXA9 are upregulated in distinct subsets of normal karyotype AML we speculated that their combined overexpression may model subsets of complex karyotype AML. We performed gene set enrichment analysis on cytogenetic subsets of previously published gene expression data from 285 AML patients. 12 of 13 Stat-related pathways were enriched in complex karyotype patients compared to 4 and 8 of 13 Stat-related pathways in inv(16) and normal karyotype AML, respectively, thus supporting a critical role of Stat activation in LSCs of AML with multiple active pathways like complex karyotype AML. In conclusion we demonstrate considerable heterogeneity of LSC fidelity depending on the number of activated oncogenes and establish a critical role of Stat1 and Stat5b in mediating this LSC fidelity. Stat1 and Stat5b may become important therapeutic targets in complex karyotype AML.

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Role of FLT3 gene mutations in acute myeloid leukemia: effect on course of disease and results of therapy

Genes and Cells ◽

10.23868/201903007 ◽

2019 ◽

Vol XIV (1) ◽

Author(s):

A.M. Radzhabova ◽

S.V. Voloshin ◽

I.S. Martynkevich ◽

A.A. Kuzyaeva ◽

V.A. Shuvaev ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Gene Mutations ◽

Course Of Disease ◽

Acute Myeloid

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Faculty Opinions recommendation of Role of altered growth factor receptor-mediated JAK2 signaling in growth and maintenance of human acute myeloid leukemia stem cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718326593.793493199 ◽

2014 ◽

Author(s):

Xiaoyan Jiang ◽

Katharina Rothe

Keyword(s):

Stem Cells ◽

Acute Myeloid Leukemia ◽

Growth Factor ◽

Myeloid Leukemia ◽

Growth Factor Receptor ◽

Leukemia Stem Cells ◽

Human Acute Myeloid Leukemia ◽

Acute Myeloid

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Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development

Experimental Hematology and Oncology ◽

10.1186/s40164-021-00233-2 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Yiyi Yao ◽

Fenglin Li ◽

Jiansong Huang ◽

Jie Jin ◽

Huafeng Wang

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chemotherapy Resistance ◽

Bone Marrow Microenvironment ◽

Cytotoxic Effects ◽

High Relapse Rate ◽

Underlying Mechanisms ◽

Acute Myeloid

AbstractDespite the advances in intensive chemotherapy regimens and targeted therapies, overall survival (OS) of acute myeloid leukemia (AML) remains unfavorable due to inevitable chemotherapy resistance and high relapse rate, which mainly caused by the persistence existence of leukemia stem cells (LSCs). Bone marrow microenvironment (BMM), the home of hematopoiesis, has been considered to play a crucial role in both hematopoiesis and leukemogenesis. When interrupted by the AML cells, a malignant BMM formed and thus provided a refuge for LSCs and protecting them from the cytotoxic effects of chemotherapy. In this review, we summarized the alterations in the bidirectional interplay between hematopoietic cells and BMM in the normal/AML hematopoietic environment, and pointed out the key role of these alterations in pathogenesis and chemotherapy resistance of AML. Finally, we focused on the current potential BMM-targeted strategies together with future prospects and challenges. Accordingly, while further research is necessary to elucidate the underlying mechanisms behind LSC–BMM interaction, targeting the interaction is perceived as a potential therapeutic strategy to eradicate LSCs and ultimately improve the outcome of AML.

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Role of CD19 and specific KIT‐D816 on risk stratification refinement in t(8;21) acute myeloid leukemia induced with different cytarabine intensities

Cancer Medicine ◽

10.1002/cam4.3705 ◽

2020 ◽

Author(s):

Biao Wang ◽

Bin Yang ◽

Yun Ling ◽

Jihong Zhang ◽

Xiaoying Hua ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Risk Stratification ◽

Myeloid Leukemia ◽

Acute Myeloid

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High HSPA8 expression predicts adverse outcomes of acute myeloid leukemia

BMC Cancer ◽

10.1186/s12885-021-08193-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jun Li ◽

Zheng Ge

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Prognostic Factor ◽

Myeloid Leukemia ◽

Cell Function ◽

Adverse Outcomes ◽

High Expression ◽

Micro Rnas ◽

Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) remains one of the most common hematological malignancies, posing a serious challenge to human health. HSPA8 is a chaperone protein that facilitates proper protein folding. It contributes to various activities of cell function and also is associated with various types of cancers. To date, the role of HSPA8 in AML is still undetermined. Methods In this study, public datasets available from the TCGA (Cancer Genome Atlas) and GEO (Gene Expression Omnibus) were mined to discover the association between the expression of HSPA8 and clinical phenotypes of CN-AML. A series of bioinformatics analysis methods, including functional annotation and miRNA-mRNA regulation network analysis, were employed to investigate the role of HSPA8 in CN-AML. Results HSPA8 was highly expressed in the AML patients compared to the healthy controls. The high HSPA8 expression had lower overall survival (OS) rate than those with low HSPA8 expression. High expression of HSPA8 was also an independent prognostic factor for overall survival (OS) of CN-AML patients by multivariate analysis. The differential expressed genes (DEGs) associated with HSPA8 high expression were identified, and they were enriched PI3k-Akt signaling, cAMP signaling, calcium signaling pathway. HSPA8 high expression was also positively associated with micro-RNAs (hsa-mir-1269a, hsa-mir-508-3p, hsa-mir-203a), the micro-RNAs targeted genes (VSTM4, RHOB, HOBX7) and key known oncogenes (KLF5, RAN, and IDH1), and negatively associated with tumor suppressors (KLF12, PRKG1, TRPS1, NOTCH1, RORA). Conclusions Our research revealed HSPA8 as a novel potential prognostic factor to predict the survival of CN-AML patients. Our data also revealed the possible carcinogenic mechanism and the complicated microRNA-mRNA network associated with the HSPA8 high expression in AML.

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