PMID- 34131281
OWN - NLM
STAT- MEDLINE
DCOM- 20211005
LR  - 20230130
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Linking)
VI  - 35
IP  - 9
DP  - 2021 Sep
TI  - Therapeutic implications of menin inhibition in acute leukemias.
PG  - 2482-2495
LID - 10.1038/s41375-021-01309-y [doi]
AB  - Menin inhibitors are novel targeted agents currently in clinical development for 
      the treatment of genetically defined subsets of acute leukemia. Menin has a tumor 
      suppressor function in endocrine glands. Germline mutations in the gene encoding 
      menin cause the multiple endocrine neoplasia type 1 (MEN1) syndrome, a hereditary 
      condition associated with tumors of the endocrine glands. However, menin is also 
      critical for leukemogenesis in subsets driven by rearrangement of the Lysine 
      Methyltransferase 2A (KMT2A) gene, previously known as mixed-lineage leukemia 
      (MLL), which encodes an epigenetic modifier. These seemingly opposing functions 
      of menin can be explained by its various roles in gene regulation. Therefore, 
      leukemias with rearrangement of KMT2A are predicted to respond to menin 
      inhibition with early clinical data validating this proof-of-concept. These 
      leukemias affect infants, children and adults, and lead to adverse outcomes with 
      current standard therapies. Recent studies have identified novel targets in acute 
      leukemia that are susceptible to menin inhibition, such as mutated Nucleophosmin 
      1 (NPM1), the most common genetic alteration in adult acute myeloid leukemia 
      (AML). In addition to these alterations, other leukemia subsets with similar 
      transcriptional dependency could be targeted through menin inhibition. This led 
      to rationally designed clinical studies, investigating small-molecule oral menin 
      inhibitors in relapsed acute leukemias with promising early results. Herein, we 
      discuss the physiologic and malignant biology of menin, the mechanisms of 
      leukemia in these susceptible subsets, and future therapeutic strategies using 
      these inhibitors in acute leukemia.
CI  - (c) 2021. The Author(s), under exclusive licence to Springer Nature Limited.
FAU - Issa, Ghayas C
AU  - Issa GC
AUID- ORCID: 0000-0002-4339-8683
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA. gcissa@mdanderson.org.
FAU - Ravandi, Farhad
AU  - Ravandi F
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - DiNardo, Courtney D
AU  - DiNardo CD
AUID- ORCID: 0000-0001-9003-0390
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Jabbour, Elias
AU  - Jabbour E
AUID- ORCID: 0000-0003-4465-6119
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Kantarjian, Hagop M
AU  - Kantarjian HM
AUID- ORCID: 0000-0002-1908-3307
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Andreeff, Michael
AU  - Andreeff M
AUID- ORCID: 0000-0002-1144-1958
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA. mandreef@mdanderson.org.
LA  - eng
GR  - K12 CA088084/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Review
DEP - 20210615
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (Antineoplastic Agents)
RN  - 0 (MEN1 protein, human)
RN  - 0 (NPM1 protein, human)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 117896-08-9 (Nucleophosmin)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Humans
MH  - Leukemia, Myeloid, Acute/*drug therapy/pathology
MH  - Molecular Targeted Therapy
MH  - Nucleophosmin
MH  - Proto-Oncogene Proteins/*antagonists & inhibitors
EDAT- 2021/06/17 06:00
MHDA- 2021/10/06 06:00
CRDT- 2021/06/16 06:40
PHST- 2021/02/28 00:00 [received]
PHST- 2021/05/24 00:00 [accepted]
PHST- 2021/05/19 00:00 [revised]
PHST- 2021/06/17 06:00 [pubmed]
PHST- 2021/10/06 06:00 [medline]
PHST- 2021/06/16 06:40 [entrez]
AID - 10.1038/s41375-021-01309-y [pii]
AID - 10.1038/s41375-021-01309-y [doi]
PST - ppublish
SO  - Leukemia. 2021 Sep;35(9):2482-2495. doi: 10.1038/s41375-021-01309-y. Epub 2021 
      Jun 15.