The Role of Hypomethylating Agents Prior to Allogeneic Hematopoietic Stem Cells Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome

Abstract Objectives The relapse of acute myeloid leukemia (AML) remains a significant concern due to persistent leukemia stem cells (LSCs) that are not targeted by existing therapies. LSCs show sensitivity to endogenous cyclopentenone prostaglandin J (CyPG) metabolites that are increased by dietary trace element selenium (Se), which is significantly decreased in AML patients. We investigated the anti-leukemic effect of Se supplementation in AML via mechanisms involving the activation of the membrane-bound G-protein coupled receptor 44 (Gpr44) and the intracellular receptor, peroxisome proliferator-activated receptor gamma (PPARγ), by endogenous CyPGs. Methods A murine model of AML generated by transplantation of hematopoietic stem cells (HSCs- WT or Gpr44−/−) expressing human MLL-AF9 fusion oncoprotein, in the following experiments: To investigate the effect of Se supplementation on the outcome of AML, donor mice were maintained on either Se-adequate (Se-A; 0.08–0.1 ppm Se) or Se-supplemented (Se-S; 0.4 ppm Se) diets. Complete cell counts in peripheral blood were analyzed by hemavet. LSCs in bone marrow and spleen were analyzed by flow cytometry. To determine the role of Gpr44 activation in AML, mice were treated with Gpr44 agonists, CyPGs. LSCs in bone marrow and spleen were analyzed. Mice transplanted with Gpr44−/- AML cells were compared with mice transplanted with wild type AML cells and the progression of the disease was followed as above. To determine the role of PPARγ activation in AML, PPARγ agonist (Rosiglitazone, 6 mg/kg, i.p, 14 d) and antagonist (GW9662, 1 mg/kg, i.p. once every other day, 7 injections) were applied to Se-S mice transplanted with Gpr44−/- AML cells and disease progression was followed. Results Se supplementation at supraphysiological levels alleviated the disease via the elimination of LSCs in a murine model of AML. CyPGs induced by Se supplementation mediate the apoptosis in LSCs via the activation of Gpr44 and PPARγ. Conclusions Endogenous CyPGs produced upon supplementation with Se at supraphysiological levels improved the outcome of AML by targeting LSCs to apoptosis via the activation of two receptors, Gpr44 and PPARg. Funding Sources NIH DK 07,7152; CA 175,576; CA 162,665. Office of Dietary Supplements, USDA Hatch funds PEN04605, Accession # 1,010,021 (KSP, RFP).

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MicroRNA-29a Is An Oncogene in Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v112.11.683.683 ◽

2008 ◽

Vol 112 (11) ◽

pp. 683-683

Author(s):

Christopher Y. Park ◽

Yoon-Chi Han ◽

Govind Bhagat ◽

Jian-Bing Fan ◽

Irving L Weissman ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Stem Cells ◽

Acute Myeloid Leukemia ◽

Hematopoietic Stem Cells ◽

Mirna Expression ◽

Myeloid Leukemia ◽

Hematopoietic Stem ◽

Acute Myeloid

Abstract microRNAs (miRNAs) are short, non-protein encoding RNAs that bind to the 3′UTR’s of target mRNAs and negatively regulate gene expression by facilitating mRNA degradation or translational inhibition. Aberrant miRNA expression is well-documented in both solid and hematopoietic malignancies, and a number of recent miRNA profiling studies have identified miRNAs associated with specific human acute myeloid leukemia (AML) cytogenetic groups as well as miRNAs that may prognosticate clinical outcomes in AML patients. Unfortunately, these studies do not directly address the functional role of miRNAs in AML. In fact, there is no direct functional evidence that miRNAs are required for AML development or maintenance. Herein, we report on our recent efforts to elucidate the role of miRNAs in AML stem cells. miRNA expression profiling of AML stem cells and their normal counterparts, hematopoietic stem cells (HSC) and committed progenitors, reveals that miR-29a is highly expressed in human hematopoietic stem cells (HSC) and human AML relative to normal committed progenitors. Ectopic expression of miR-29a in mouse HSC/progenitors is sufficient to induce a myeloproliferative disorder (MPD) that progresses to AML. During the MPD phase of the disease, miR-29a alters the composition of committed myeloid progenitors, significantly expedites cell cycle progression, and promotes proliferation of hematopoietic progenitors at the level of the multipotent progenitor (MPP). These changes are manifested pathologically by marked granulocytic and megakaryocytic hyperplasia with hepatosplenomegaly. Mice with miR-29a-induced MPD uniformly progress to an AML that contains a leukemia stem cell (LSC) population that can serially transplant disease with as few as 20 purified LSC. Gene expression analysis reveals multiple tumor suppressors and cell cycle regulators downregulated in miR-29a expressing cells compared to wild type. We have demonstrated that one of these genes, Hbp1, is a bona fide miR-29a target, but knockdown of Hbp1 in vivo does not recapitulate the miR-29a phenotype. These data indicate that additional genes are required for miR-29a’s leukemogenic activity. In summary, our data demonstrate that miR-29a regulates early events in normal hematopoiesis and promotes myeloid differentiation and expansion. Moreover, they establish that misexpression of a single miRNA is sufficient to drive leukemogenesis, suggesting that therapeutic targeting of miRNAs may be an effective means of treating myeloid leukemias.

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A New Entity of Acute Myeloid Leukemia Driven By Epigenetic and Somatic Dis-Regulation of Uncx, a Novel Homeobox Transcription Factor Gene

Blood ◽

10.1182/blood.v126.23.1356.1356 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1356-1356

Author(s):

Giulia Daniele ◽

Clelia Tiziana Storlazzi ◽

Cristina Papayannidis ◽

Ilaria Iacobucci ◽

Angelo Lonoce ◽

...

Keyword(s):

Stem Cells ◽

Acute Myeloid Leukemia ◽

Transcription Factor ◽

Myeloid Leukemia ◽

De Novo ◽

Ectopic Expression ◽

Response To Therapy ◽

Hematopoietic Stem ◽

Acute Myeloid

Abstract We describe a new AML entity, occurring in 30% of de novo acute myeloid leukemia, due to structural and epigenetic deregulation of the UNCX homeobox (HB) gene. By molecular approaches, we identified a M5 AML patient with a t(7;10)(p22;p14) translocation as the sole cytogenetic anomaly and showing ectopic expression of UNCX (7p22.3), which encode for a transcription factor involved in somitogenesis and neurogenesis. Since UNCX was never reported in association with cancer but only with common myeloid cell proliferation and regulation of cell differentiation, we decided to investigate its contribution to leukemogenesis. We observed UNCX ectopic expression in 32.3% (20/62) and in 8% (6/75) of acute myeloid leukemia (AML) patients and cell lines, respectively. Notably, retroviral-mediated UNCX transfer in CD34+ HSCs induced a slow-down in their proliferation and differentiation and transduced cells showed a lower growth rate but a higher percentage of CD34+ stem cells in liquid culture than controls. Additionally, UNCX infected cells displayed a decrease of MAP2K1 proliferation marker but increase of KLF4, HOXA10, and CCNA1, associated with impaired differentiation and pluripotency. Similarly, UNCX-positive patients revealed alteration of gene pathways involved in proliferation, cell cycle control and hematopoiesis. Since HB genes encode for transcription factors showing a crucial role in normal hematopoiesis and in leukemogenesis, we focused our attention on the role of altered UNCX expression level. Of note, its murine ortholog, (Uncx) was previously described as embedded within a low-methylated regions (≤ 10%) called "canyon" and dysregulated in murine hematopoietic stem cells (HSCs) as a consequence of altered methylation at canyons edges (borders) due to Dnmt3a inactivation. In our hands, UNCX activation was accompanied by methylation changes at both its canyon borders, clearly indicating an epigenetic regulation of this gene, although not induced by DNMT3A mutations. Clinical parameters and correlation with response to therapy will be presented. Taken together, our results indicate that more than 30% of de novo AML have a novel entity with a putative leukemogenic role of UNCX, whose activation may be ascribed to epigenetic regulators. Acknowledgments: MG, CP, GS, and AP(2) and this work was supported by ELN, AIL, AIRC, progetto Regione-Università 2010-12 (L. Bolondi), Fondazione del Monte di Bologna e Ravenna, FP7 NGS-PTL project. CTS, GD and AL are supported by Associazione Italiana Ricerca sul Cancro (AIRC) funding. Disclosures Nadarajah: MLL Munich Leukemia Laboratory: Employment. Martinelli:MSD: Consultancy; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; AMGEN: Consultancy; ROCHE: Consultancy.

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CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia

International Journal of Molecular Sciences ◽

10.3390/ijms20235826 ◽

2019 ◽

Vol 20 (23) ◽

pp. 5826 ◽

Cited By ~ 2

Author(s):

Tobias Gluexam ◽

Alexander M. Grandits ◽

Angela Schlerka ◽

Chi Huu Nguyen ◽

Julia Etzler ◽

...

Keyword(s):

Stem Cells ◽

Acute Myeloid Leukemia ◽

Stem Cell ◽

Mouse Model ◽

Cell Lines ◽

Myeloid Leukemia ◽

Leukemic Cells ◽

Hematopoietic Stem ◽

Acute Myeloid

The neuropeptide CGRP, acting through the G-protein coupled receptor CALCRL and its coreceptor RAMP1, plays a key role in migraines, which has led to the clinical development of several inhibitory compounds. Recently, high CALCRL expression has been shown to be associated with a poor prognosis in acute myeloid leukemia (AML). We investigate, therefore, the functional role of the CGRP-CALCRL axis in AML. To this end, in silico analyses, human AML cell lines, primary patient samples, and a C57BL/6-based mouse model of AML are used. We find that CALCRL is up-regulated at relapse of AML, in leukemic stem cells (LSCs) versus bulk leukemic cells, and in LSCs versus normal hematopoietic stem cells. CGRP protects receptor-positive AML cell lines and primary AML samples from apoptosis induced by cytostatic drugs used in AML therapy, and this effect is inhibited by specific antagonists. Furthermore, the CGRP antagonist olcegepant increases differentiation and reduces the leukemic burden as well as key stem cell properties in a mouse model of AML. These data provide a basis for further investigations into a possible role of CGRP-CALCRL inhibition in the therapy of AML.

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Myelodysplastic Syndrome / Secondary Acute Myeloid Leukemia: role of the allogeneic hematopoietic stem cell transplantation

JBMTCT ◽

10.46765/2675-374x.2020v1n1p15-18 ◽

2020 ◽

Vol 1 (1) ◽

pp. 15-18

Author(s):

Yhasmine Delles Oliveira Garcia ◽

Juliene Lima Mesquita ◽

Yensy Mariana Zelaya Rosales ◽

Anna Thawanny Gadelha Moura ◽

Beatriz Stela Gomes de Sousa Pitombeira Araujo ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Myelodysplastic Syndrome ◽

Hematopoietic Stem Cell ◽

Myeloid Leukemia ◽

Hematopoietic Stem ◽

Secondary Acute Myeloid Leukemia ◽

Blast Cells ◽

Acute Myeloid

Secondary Acute Myeloid Leukemia (s-AML) refers to the development of leukemia after cytotoxic therapy, immunosuppressive therapy, radiation or an antecedent hematological disorder, such as Myelodysplastic Syndrome (MDS). A s-AML corresponds to 10% to 30% of AML cases and is defined by the presence of at least 20% of blast cells, representing a category of disease with a poor prognosis. Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only option with curative potential for patients with s-AML, but recurrence after HSCT emerges as a frequent cause of treatment failure and course with high mortality. We report the case of a patient with s-AML after MDS, who underwent HSCT due to refractoriness to other treatments, recovering the bone marrow with dysplasia, being classified as AREB1.

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Duration to Engraftment Requires Significantly Much More Time in Myelodysplastic Syndrome (MDS) Patients as Compared to Acute Myeloid Leukemia (AML) Patients Following Allogeneic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v106.11.5326.5326 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5326-5326

Author(s):

Menachem Bitan ◽

Michael Y. Shapira ◽

Igor B. Resnick ◽

Benjamin Gesundheit ◽

Irena Zilberman ◽

...

Keyword(s):

Stem Cells ◽

Acute Myeloid Leukemia ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Myelodysplastic Syndrome ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Myeloid Leukemia ◽

Hematopoietic Stem ◽

Acute Myeloid

Abstract Normal hematopoiesis is characterized by the balanced interplay between hematopoietic stem cells and the cells and molecules that forms part of the microenvironment in which blood cell production takes place. Myelodysplastic syndrome (MDS) marrow stroma cells are known to fail in supporting the growing of normal stem cells. We therefore retrospectively analyzed the duration to engraftment of absolute neutrophil count (ANC) ≥0.5 x 109/L and ≥1.0 x 109/L and the time interval to platelet recovery of ≥20 and ≥50 x 109/L in 42 MDS patients as compared to 42 patients suffering from primary acute myeloid leukemia (AML), following allogeneic stem cell transplantation (SCT). Significant shorter time to engraftment was documented in AML as compared to MDS patients in all 4 parameters. These results hold true even if we sub-grouped the patients according to gender, age, with the age of 50 years old being the cutoff between young and elderly patients, or when the donor was related to the patient. Moreover, sub-grouping the patients from each diagnosis according to the conditioning regimens that were given prior to transplantation revealed the same significant better results for the AML patients when received a non-myeloablative regimen. To the best of our knowledge, this is the first time that such a comparison is being made. We suggest that duration to engraftment in MDS patients takes significantly longer time and this may influence and worsen their course of transplantation in terms of morbidity as well as mortality.

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