PMID- 34587239
OWN - NLM
STAT- MEDLINE
DCOM- 20220411
LR  - 20220716
IS  - 2473-9537 (Electronic)
IS  - 2473-9529 (Print)
IS  - 2473-9529 (Linking)
VI  - 6
IP  - 3
DP  - 2022 Jan 8
TI  - t(4;12)(q12;p13) ETV6-rearranged AML without eosinophilia does not involve 
      PDGFRA: relevance for imatinib insensitivity.
PG  - 818-827
LID - 10.1182/bloodadvances.2021005280 [doi]
AB  - Acute myeloid leukemia (AML) with t(4;12)(q12;p13) translocation is rare and 
      often associated with an aggressive clinical course and poor prognosis. Previous 
      reports based on fluorescence in situ hybridization (FISH) analysis have 
      suggested that ETV6::PDGFRA fusions are present in these patients, despite the 
      absence of eosinophilia, which is typically found in other hematopoietic 
      malignancies with PDGFRA-containing fusions. We first detected an ETV6-SCFD2 
      fusion by targeted RNA sequencing in a patient with t(4;12)(q12;p13) who had been 
      diagnosed with an ETV6-PDGFRA fusion by FISH analysis but failed to respond to 
      imatinib. We then retrospectively identified 4 additional patients with AML and 
      t(4;12)(q12;p13) with apparent ETV6-PDGFRA fusions using chromosome and FISH 
      analysis and applied targeted RNA sequencing to archival material. We again 
      detected rearrangements between ETV6 and non-PDGFRA 4q12 genes, including SCFD2, 
      CHIC2, and GSX2. None of the 3 patients who received imatinib based on the 
      incorrect assumption of an ETV6-PDGFRA fusion responded. Our findings highlight 
      the importance of using a sequencing-based assay to confirm the presence of 
      targetable gene fusions, particularly in genomic regions, such as 4q12, with many 
      clinically relevant genes that are too close to resolve by chromosome or FISH 
      analysis. Finally, combining our data and review of the literature, we show that 
      sequence-confirmed ETV6-PDGFRA fusions are typically found in eosinophilic 
      disorders (3/3 cases), and patients with t(4;12)(q12;p13) without eosinophilia 
      are found to have other 4q12 partners on sequencing (17/17 cases).
CI  - (c) 2022 by The American Society of Hematology. Licensed under Creative Commons 
      Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), 
      permitting only noncommercial, nonderivative use with attribution. All other 
      rights reserved.
FAU - Mueller, Sarah B
AU  - Mueller SB
AUID- ORCID: 0000-0002-7985-2155
AD  - Department of Pathology, Massachusetts General Hospital, Boston, MA.
FAU - Dal Cin, Paola
AU  - Dal Cin P
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, MA.
FAU - Le, Long P
AU  - Le LP
AD  - Department of Pathology, Massachusetts General Hospital, Boston, MA.
FAU - Dias-Santagata, Dora
AU  - Dias-Santagata D
AD  - Department of Pathology, Massachusetts General Hospital, Boston, MA.
FAU - Lennerz, Jochen K
AU  - Lennerz JK
AUID- ORCID: 0000-0003-2434-4978
AD  - Department of Pathology, Massachusetts General Hospital, Boston, MA.
FAU - Iafrate, A John
AU  - Iafrate AJ
AD  - Department of Pathology, Massachusetts General Hospital, Boston, MA.
FAU - Marble, Hetal Desai
AU  - Marble HD
AUID- ORCID: 0000-0001-8203-0622
AD  - Department of Pathology, Massachusetts General Hospital, Boston, MA.
FAU - Brunner, Andrew M
AU  - Brunner AM
AD  - Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA.
FAU - Weinstock, Matthew J
AU  - Weinstock MJ
AD  - Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA; 
      and.
FAU - Luskin, Marlise R
AU  - Luskin MR
AUID- ORCID: 0000-0002-5781-4529
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
FAU - De Angelo, Daniel J
AU  - De Angelo DJ
AUID- ORCID: 0000-0001-7865-2306
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
FAU - Stone, Richard M
AU  - Stone RM
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
FAU - Nardi, Valentina
AU  - Nardi V
AD  - Department of Pathology, Massachusetts General Hospital, Boston, MA.
LA  - eng
GR  - P50 CA206963/CA/NCI NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Blood Adv
JT  - Blood advances
JID - 101698425
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - *Eosinophilia/genetics
MH  - Humans
MH  - Imatinib Mesylate/pharmacology/therapeutic use
MH  - In Situ Hybridization, Fluorescence
MH  - *Leukemia, Myeloid, Acute/genetics
MH  - Receptor Protein-Tyrosine Kinases
MH  - Retrospective Studies
PMC - PMC8945303
EDAT- 2021/09/30 06:00
MHDA- 2022/04/12 06:00
PMCR- 2022/02/01
CRDT- 2021/09/29 17:24
PHST- 2021/05/17 00:00 [received]
PHST- 2021/07/14 00:00 [accepted]
PHST- 2021/09/30 06:00 [pubmed]
PHST- 2022/04/12 06:00 [medline]
PHST- 2021/09/29 17:24 [entrez]
PHST- 2022/02/01 00:00 [pmc-release]
AID - 477073 [pii]
AID - 2022/ADV2021005280 [pii]
AID - 10.1182/bloodadvances.2021005280 [doi]
PST - ppublish
SO  - Blood Adv. 2022 Jan 8;6(3):818-827. doi: 10.1182/bloodadvances.2021005280.