TO THE EDITOR:FMS-like receptor tyrosine kinase 3 (FLT3) expression is almost exclusively found in the myeloid compartment [1]. The FLT3 protein consists of an extracellular region containing the ligand-binding site, a transmembrane domain, a cytoplasmic juxtamembrane domain, and a tyrosine kinase domain (TKD).

致编辑：FMS样受体酪氨酸激酶3（FLT3）的表达几乎完全存在于髓样区室（1）。FLT3蛋白由含有配体结合位点的细胞外区域，跨膜结构域，细胞质近膜结构域和酪氨酸激酶结构域（TKD）组成。

Being a proto-oncogene, gain-of-function mutations in FLT3 (FLT3MT) gene create a robust selection pressure on affected myeloid leukemic precursors by alleviating the need for ligand binding [2].FLT3MT occurs in about 30% of acute myeloid leukemia (AML) cases, with internal tandem duplications (ITD; FLT3ITD) accounting for 80% of all FLT3MT cases.

作为原癌基因，FLT3（FLT3MT）基因的功能获得性突变通过减轻配体结合的需要，对受影响的髓系白血病前体产生了强大的选择压力。FLT3MT发生在约30%的急性髓细胞白血病（AML）病例中，内部串联重复（ITD；FLT3ITD）占所有FLT3MT病例的80%。

In addition to FLT3ITD, distinct point mutations and deletions within the TKD, and more specifically mutations occurring in the activation loop (AL; FLT3AL) of the TKD can occur. Nonetheless, the latter are less common, making up approximately 7–10% of all AML cases [3]. FLT3MT has been linked to unfavorable prognoses [2], but recently, various FLT3 tyrosine kinase inhibitors (TKIs) of varying selectivity have been developed and their application may mitigate some unfavorable prognostic features of FLT3ITD and FLT3AL in the setting of myeloid neoplasms (MNs) [3, 4].

除FLT3ITD外，还可能发生TKD内不同的点突变和缺失，更具体地说，可能发生在TKD的激活环（AL；FLT3AL）中的突变。尽管如此，后者并不常见，约占所有AML病例的7-10%[3]。FLT3MT与不良预后有关，但最近，已经开发出各种选择性不同的FLT3酪氨酸激酶抑制剂（TKIs），它们的应用可能会减轻FLT3ITD和FLT3AL在髓系肿瘤（MNs）中的一些不良预后特征[3，4]。

“Non-canonical” FLT3MT (NC; FLT3NC), i.e., not being ITD or located outside of the AL, have only occasionally been found in AML and related MNs [5]. However, the prognostic impact and clinical implications of such atypical molecular alterations have been far less explored than typical ITD and AL defects [2, 5,6,7].

“非规范”FLT3MT（NC；FLT3NC），即不属于ITD或位于AL之外，仅偶尔在AML和相关MN中发现（5）。然而，这种非典型分子改变的预后影响和临床意义远不如典型的ITD和AL缺陷[2，5，6，7]。

We conducted a systematic analysis of the molecular landscape of FLT3MT, including FLT3NC, in a cohort of MN patients.When we conducted a molecular and clinical analysis of 4529 patients with diverse MN subtypes (Tables S1 [excel format] and S2), .

我们对MN患者队列中FLT3MT（包括FLT3NC）的分子景观进行了系统分析。当我们对4529名不同MN亚型的患者进行分子和临床分析时（表S1[excel格式]和S2）。

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Wing Hing Wong. Physiologic and pathologic profiling of clonal variations (2019).Download referencesFundingThe authors thank The Leukemia & Lymphoma Society TRP Award 6645-22 (to J.P.M.), R35 R35HL135795 (to J.P.M.), and AAMDSIF grant (to C.B-P., V.V.). C.B-P. has a postdoctoral fellowship from Instituto de Salud Carlos III (JR22/00041).Author informationAuthor notesThese authors contributed equally: Valeria Visconte, Jaroslaw P.

。克隆变异的生理和病理分析（2019）。下载参考文献资助作者感谢白血病与淋巴瘤协会TRP奖6645-22（致J.P.M.），R35 R35HL135795（致J.P.M.）和AAMDSIF赠款（致C.B-P.，V.V.）。C、 B-P.拥有萨卢德·卡洛斯三世研究所的博士后奖学金（JR22/00041）。作者信息作者注意到这些作者做出了同样的贡献：Valeria Visconte，Jaroslaw P。

MaciejewskiAuthors and AffiliationsDepartment of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USAJaymeson Gordon, Carlos Bravo-Perez, Luca Guarnera, Serhan Unlu, Naomi Kawashima, Arooj Ahmed, Christopher Haddad, Yasuo Kubota, Ishani Nautiyal, Fauzia Ullah, Danai Dima, Nakisha D.

MaciejewskiAuthors and affiliations转化血液学和肿瘤学研究部，塔西格癌症研究所，克利夫兰诊所，克利夫兰，俄亥俄州，USAJaymeson Gordon，Carlos Bravo Perez，Luca Guarnera，Serhan Unlu，Naomi Kawashima，Arooj Ahmed，Christopher Haddad，Yasuo Kubota，Ishani Nautiyal，Fauzia Ullah，Danai Dima，Nakisha D。

Williams, Carmelo Gurnari, Valeria Visconte & Jaroslaw P. MaciejewskiDepartment of Hematology and Medical Oncology, Hospital Universitario Morales Meseguer, University of Murcia, IMIB-Pascual Parrilla, CIBERER - Instituto de Salud Carlos III, Murcia, SpainCarlos Bravo-PerezDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, ItalyLuca Guarnera & Carmelo GurnariDepartment of Hematology and Medical Oncology, Yale University, New Haven, CT, USATariq KewanDivision of Medical Oncology & Hematology, School of Medicine University of Louisville, Louisville, KY, USAWaled BahajLeukemia Program, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USAHetty E.

。

CarrawayDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USAChao-Yie YangAuthorsJaymeson GordonView author publicationsYou can also search for this author in.

美国田纳西州孟菲斯市田纳西大学健康科学中心药学院药物科学系Chao Yie YangAuthorsJaymeson GordonView作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsJ.G. collected, analyzed, interpreted data, and wrote the manuscript; C.B-P., L.G. collected data and wrote the manuscript. S.U., A.A., C.H. collected clinical data and edited the manuscript; Y.K., N.D.W. I.N., F.U., D.D., T.K., W.B. collected molecular data; H.E.C., C.G.

PubMed谷歌学术贡献。G、 收集，分析，解释数据并撰写手稿；C、 B-P.，L.G.收集数据并撰写手稿。S、 U.，A.A.，C.H.收集临床数据并编辑手稿；Y、 K.，N.D.W.I.N.，F.U.，D.D.，T.K.，W.B.收集的分子数据；H、 E.C.，C.G。

provided helpful insights and edited the manuscript; C-Y.Y. performed in silico protein prediction and edited the manuscript; V.V., J.P.M. designed the study, conceptualized, interpreted data, and wrote the manuscript. All authors read and approved the final version of the manuscript. C.G. was supported by a grant from the Edward P.

提供了有益的见解并编辑了手稿；C-Y.Y.进行了计算机蛋白质预测并编辑了手稿；五、 V.，J.P.M.设计了这项研究，概念化，解释了数据，并撰写了手稿。所有作者都阅读并批准了稿件的最终版本。C、 G.得到了Edward P.的资助。

Evans Foundation.Corresponding authorCorrespondence to.

埃文斯基金会。对应作者对应。

Jaroslaw P. Maciejewski.Ethics declarations

Jaroslaw P.Maciejewski。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Consent for publication

同意出版

Informed consent was obtained according to the protocols approved by the Institutional Review Board of the Cleveland Clinic Foundation and in accordance with the ethical principles set forth by the Declaration of Helsinki.

根据克利夫兰诊所基金会机构审查委员会批准的协议以及《赫尔辛基宣言》规定的道德原则，获得了知情同意。

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Reprints and permissionsAbout this articleCite this articleGordon, J., Bravo-Perez, C., Guarnera, L. et al. Non-canonical FLT3 alterations reveal novel germline FLT3 variants leading to somatic gene rescue mutations.

转载和许可本文引用本文Gordon，J.，Bravo-Perez，C.，Guarnera，L。等人。非经典FLT3改变揭示了导致体细胞基因拯救突变的新型种系FLT3变体。

Blood Cancer J. 14, 125 (2024). https://doi.org/10.1038/s41408-024-01104-9Download citationReceived: 15 May 2024Revised: 05 July 2024Accepted: 15 July 2024Published: 30 July 2024DOI: https://doi.org/10.1038/s41408-024-01104-9Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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