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Sökning: WFRF:(Bengtzén Sofia) > A new mutant NPM1/I...

A new mutant NPM1/IDH2R140- and PML-RARA-associated lncRNA MALNC plays a role in AML biology, prognosis and drug response

Neddermeyer, Anne (författare)
Uppsala universitet,Institutionen för medicinska vetenskaper,Sören Lehmann
Björklund, My (författare)
Uppsala universitet,Institutionen för medicinska vetenskaper,Sören Lehmann
Dimitris, Kanellis (författare)
Department of Biochemistry and Biophysics, Solna, Karolinska Institute,Jiri Bartek
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Struyf, Nona (författare)
Department of Oncology-Pathology, Karolinska Institute, Solna, Sweden,Päivi Östling
Karlsson, Kasper (författare)
Department of Oncology-Pathology, Karolinska Institute, Solna, Sweden,Olli-Pekka Kallioniemi
Qu, Ying (författare)
Department of Medicine, Karolinska Institute, Huddinge, Sweden,Sören Lehmann
Mareschal, Sylvain (författare)
LYSARC, The Lymphoma Academic Research Organization, Lyon, France
Cozzi, Elisabetta (författare)
Department of Medicine, Karolinska Institute, Solna, Sweden,Sören Lehmann
Zhong, Xiangfu (författare)
Department of Medicine, Karolinska Institute, Huddinge, Sweden,Sören Lehmann
Bengtzén, Sofia (författare)
Department of Medicine, Karolinska Institute, Huddinge, Sweden,Sören Lehmann
Nilsson, Christer (författare)
Department of Medicine, Karolinska Institute, Huddinge, Sweden,Sören Lehmann
Erkers, Tom (författare)
Department of Oncology-Pathology, Karolinska Institute, Solna, Sweden,Olli-Pekka Kallioniemi
Kallioniemi, Olli-Pekka (författare)
Department of Oncology-Pathology, Karolinska Institute, Solna, Sweden,Olli-Pekka Kallioniemi
Lennartsson, Andreas (författare)
Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden,Andreas Lennartsson
Lehmann, Sören (författare)
Uppsala universitet,Institutionen för medicinska vetenskaper,Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden,Sören Lehmann
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 (creator_code:org_t)
Engelska.
  • Annan publikation (övrigt vetenskapligt/konstnärligt)
Abstract Ämnesord
Stäng  
  • Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by poor prognosis that requires better understanding of its disease biology and new tools for suitable risk stratification and effective treatments. Long non-coding RNAs (lncRNAs) are involved in numerous molecular mechanisms, are implicated in tumor biology and can serve as clinical biomarkers, yet their role remains mostly unclear in AML. In this study, the aim was to discover and characterize lncRNAs implicated in AML and to describe their role in AML biology. Further aims were to explore their use as prognostic or predictive biomarkers. Using whole-transcriptome analysis, a novel lncRNA, here named MALNC, was identified. MALNC had elevated expression in two large AML cohorts compared to normal CD34+ cells. Clinical correlation analyses indicated that MALNC was almost uniquely expressed in patients with PML-RARA fusion gene and with co-mutated isocitrate dehydrogenase-2 R140 and nucleophosmin-1 (IDH2R140/NPM1). MALNC expression was specifically high at the promyelocytic stage and decreased with maturation in leukemic and normal cells. High MALNC expression associated independently with better overall survival. CRISPR-Cas9-knockout in promyelocytic cell lines impaired proliferation, colony formation and all-trans retinoic acid (ATRA)-induced differentiation. Also, MALNC-knockout dramatically sensitized cells to arsenic trioxide (ATO), ATO-ATRA combinatorial and Bcl-2-inhibitor venetoclax treatment as well as associated with cyclin-dependent kinase (Cdk)-inhibitor resistance. In conclusion, MALNC is overexpressed in certain subgroups of AML and could play a role during normal and leukemic hematopoietic maturation. Furthermore, it correlates with response to anti-leukemic drugs, which suggests a role as a predictive marker to drug response and survival in AML.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Hematologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Hematology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Nyckelord

acute myeloid leukemia (AML)
long non-coding RNAs (lncRNAs)
RNA-sequencing
CRISPR-Cas9
all-trans retinoic acid (ATRA)
arsenic trioxide (ATO)
venetoclax
drug response
prognosis
Molekylär medicin
Molecular Medicine

Publikations- och innehållstyp

vet (ämneskategori)
ovr (ämneskategori)

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