scholarly journals Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia

Science ◽  
2020 ◽  
Vol 367 (6477) ◽  
pp. 586-590 ◽  
Author(s):  
Hannah J. Uckelmann ◽  
Stephanie M. Kim ◽  
Eric M. Wong ◽  
Charles Hatton ◽  
Hugh Giovinazzo ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Progenitor Cell ◽  
Epigenetic Therapy ◽  
Preventative Treatment ◽  
Self Renewal ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cell ◽  
Progenitor Cell Proliferation ◽  
Acute Myeloid

The initiating mutations that contribute to cancer development are sometimes present in premalignant cells. Whether therapies targeting these mutations can eradicate premalignant cells is unclear. Acute myeloid leukemia (AML) is an attractive system for investigating the effect of preventative treatment because this disease is often preceded by a premalignant state (clonal hematopoiesis or myelodysplastic syndrome). In Npm1c/Dnmt3a mutant knock-in mice, a model of AML development, leukemia is preceded by a period of extended myeloid progenitor cell proliferation and self-renewal. We found that this self-renewal can be reversed by oral administration of a small molecule (VTP-50469) that targets the MLL1-Menin chromatin complex. These preclinical results support the hypothesis that individuals at high risk of developing AML might benefit from targeted epigenetic therapy in a preventative setting.

scholarly journals Association of Nucleophosmin-1 (NPM1) Expression with Leucocyte Count, Blast Count, and Gingiva Hypertrophy in Acute Myeloid Leukemia De Novo Patients in General Hospital of Dr M Djamil Padang Indonesia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5171-5171
Author(s):  
Irza Wahid ◽  
Tubagus Djumhana Atmakusuma
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Progenitor Cell ◽  
Leucocyte Count ◽  
De Novo ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cell ◽  
Gingival Hypertrophy ◽  
Blast Count ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a malignant disease derived from hematopoietic system characterized by neoplastic transformation of myeloid progenitor cell, present as excessive proliferation and differentiation alteration leading to inhibition of myeloid maturation. From various studies, incident and prevalence of AML these days is increasing in morbidity and mortality. This make AML known with poor prognosis. Nucleophosmin-1 (NPM-1) was established by WHO revision 2016 as prognostic gene marker in AML. Nucleophosmin-1 gene is mutated in 35-60% of AML cases. Recently, molecular biologic development suggests that prognostic gene examination is needed to reduce morbidity and mortality of AML patients. If myeloid progenitor cell encounters carcinogenic/leukemogenic stresses, mutation of several genes could happen. NPM1 gene is a likely mutated gene and predominantly located in nucleolus. Overexpression of NPM1 will promote activities of tumor suppressors like P53, ARF and MDM2. Interactions of those tumor suppressors promote proliferation, differentiation, cell survival, apoptosis and DNA repair, which give a better prognosis in AML patients. To study about association of NPM1 expression with leucocyte count, blast count, and gingiva hypertrophy in AML de novo patients in general hospital of Dr M Djamil Padang, Indonesia. Analytic observational study with cross-sectional approach to 25 adult AML patients from Policlinic and Inpatient Installation of Dr M Djamil Hospital from March to August 2018 who met inclusion and exclusion criteria. Expression of NPM1 was measured with qRT-PCR. We found significant increase of NPM1 expression in AML in the amount of 22.62x107 copies/ml. There was a significant very strong correlation between NPM1 expression and leucocyte count (p<0.05 & r=0.870) and blast count (p<0.05 & r=0.828). There was also significant differences of NPM1 expression in AML patients with gingival hypertrophy and without gingival hypertrophy (31.3 x 107 copies/ml dan 9.6 x 107 copies/ml). There was a significant very strong correlation between NPM1 expression with leucocyte count and blast count. There was significant increases of NPM1 expression in AML patients with gingival hypertrophy. Keywords: acute myeloid leukemia, Nucleophosmin-1, leucocyte, blast, gingival hypertrophy Disclosures No relevant conflicts of interest to declare.

scholarly journals A KDM4A-PAF1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Matthew E. Massett ◽  
Laura Monaghan ◽  
Shaun Patterson ◽  
Niamh Mannion ◽  
Roderick P. Bunschoten ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cell Activity ◽  
Leukemia Cell ◽  
Gene Signature ◽  
Pathological Feature ◽  
Self Renewal ◽  
Stem Cell Activity ◽  
Molecular Mechanism Of Action ◽  
Acute Myeloid

AbstractEpigenomic dysregulation is a common pathological feature in human hematological malignancies. H3K9me3 emerges as an important epigenomic marker in acute myeloid leukemia (AML). Its associated methyltransferases, such as SETDB1, suppress AML leukemogenesis, whilst H3K9me3 demethylases KDM4C is required for mixed-lineage leukemia rearranged AML. However, the specific role and molecular mechanism of action of another member of the KDM4 family, KDM4A has not previously been clearly defined. In this study, we delineated and functionally validated the epigenomic network regulated by KDM4A. We show that selective loss of KDM4A is sufficient to induce apoptosis in a broad spectrum of human AML cells. This detrimental phenotype results from a global accumulation of H3K9me3 and H3K27me3 at KDM4A targeted genomic loci thereby causing downregulation of a KDM4A-PAF1 controlled transcriptional program essential for leukemogenesis, distinct from that of KDM4C. From this regulatory network, we further extracted a KDM4A-9 gene signature enriched with leukemia stem cell activity; the KDM4A-9 score alone or in combination with the known LSC17 score, effectively stratifies high-risk AML patients. Together, these results establish the essential and unique role of KDM4A for AML self-renewal and survival, supporting further investigation of KDM4A and its targets as a potential therapeutic vulnerability in AML.

scholarly journals RSPO2 inhibits BMP signaling to promote self-renewal in acute myeloid leukemia

Cell Reports ◽  
2021 ◽  
Vol 36 (7) ◽  
pp. 109559
Author(s):  
Rui Sun ◽  
Lixiazi He ◽  
Hyeyoon Lee ◽  
Andrey Glinka ◽  
Carolin Andresen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bmp Signaling ◽  
Self Renewal ◽  
Acute Myeloid

scholarly journals Minimal residual disease eradication with epigenetic therapy in core binding factor acute myeloid leukemia

2017 ◽  
Vol 92 (9) ◽  
pp. 845-850 ◽  
Author(s):  
Brittany Knick Ragon ◽  
Naval Daver ◽  
Guillermo Garcia-Manero ◽  
Farhad Ravandi ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Epigenetic Therapy ◽  
Core Binding Factor ◽  
Disease Eradication ◽  
Binding Factor ◽  
Minimal Residual ◽  
Acute Myeloid

scholarly journals The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;NrasG12D acute myeloid leukemia

Oncogene ◽  
2012 ◽  
Vol 32 (7) ◽  
pp. 930-938 ◽  
Author(s):  
J Shi ◽  
E Wang ◽  
J Zuber ◽  
A Rappaport ◽  
M Taylor ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mouse Model ◽  
Myeloid Leukemia ◽  
Self Renewal ◽  
Polycomb Complex ◽  
Acute Myeloid

scholarly journals Repurposing Drugs for Acute Myeloid Leukemia: A Worthy Cause or a Futile Pursuit?

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 441 ◽  
Author(s):  
Anna V. Wojcicki ◽  
Meena Kadapakkam ◽  
Adam Frymoyer ◽  
Norman Lacayo ◽  
Hee-Don Chae ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Unmet Need ◽  
Current Treatment ◽  
Secondary Effects ◽  
Chemotherapy Drugs ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Alternative Drug ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a clinically and genetically heterogenous malignancy of myeloid progenitor cells that affects patients of all ages. Despite decades of research and improvement in overall outcomes, standard therapy remains ineffective for certain subtypes of AML. Current treatment is intensive and leads to a number of secondary effects with varying results by patient population. Due to the high cost of discovery and an unmet need for new targeted therapies that are well tolerated, alternative drug development strategies have become increasingly attractive. Repurposing existing drugs is one approach to identify new therapies with fewer financial and regulatory hurdles. In this review, we provide an overview of previously U.S. Food and Drug Administration (FDA) approved non-chemotherapy drugs under investigation for the treatment of AML.

scholarly journals microRNA-29a induces aberrant self-renewal capacity in hematopoietic progenitors, biased myeloid development, and acute myeloid leukemia

2010 ◽  
Vol 207 (3) ◽  
pp. 475-489 ◽  
Author(s):  
Yoon-Chi Han ◽  
Christopher Y. Park ◽  
Govind Bhagat ◽  
Jinping Zhang ◽  
Yulei Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Ectopic Expression ◽  
Hematopoietic Progenitors ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Myeloid Development ◽  
Acute Myeloid ◽  
Myeloid Progenitors

The function of microRNAs (miRNAs) in hematopoietic stem cells (HSCs), committed progenitors, and leukemia stem cells (LSCs) is poorly understood. We show that miR-29a is highly expressed in HSC and down-regulated in hematopoietic progenitors. Ectopic expression of miR-29a in mouse HSC/progenitors results in acquisition of self-renewal capacity by myeloid progenitors, biased myeloid differentiation, and the development of a myeloproliferative disorder that progresses to acute myeloid leukemia (AML). miR-29a promotes progenitor proliferation by expediting G1 to S/G2 cell cycle transitions. miR-29a is overexpressed in human AML and, like human LSC, miR-29a-expressing myeloid progenitors serially transplant AML. Our data indicate that miR-29a regulates early hematopoiesis and suggest that miR-29a initiates AML by converting myeloid progenitors into self-renewing LSC.

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