Zheng Rui, Klang Kendra, Gorin Norbert C, Small Donald
Department of Pediatric Oncology, Johns Hopkins University School of Medicine, Room 253, Bunting-Blaustein Cancer Research Building, Baltimore, MD 21231-1000, USA.
Leuk Res. 2004 Feb;28(2):121-6. doi: 10.1016/s0145-2126(03)00184-x.
KIT and FMS, members of the class III receptor tyrosine kinase family, are expressed on normal hematopoietic cells and have important roles in normal hematopoiesis. FLT3 is also a member of the class III receptor tyrosine kinase family and plays important role in hematopoietic stem/progenitor cells, NK, and dendritic cells. Recently, internal tandem duplication (ITDs) mutations have been found in the juxtamembrane (JM) region of FLT3 receptor expressed by patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The mutations result in the constitutive dimerization and activation of the receptor, contributing to leukemic transformation. KIT and FMS are also frequently expressed in AML and are closely related to FLT3. Thus, similar ITD mutations could also occur in the KIT and/or FMS gene of patients with AML. To explore this possibility, 13 human leukemia-lymphoma cell lines and 44 AML patient samples were examined by reverse transcription-polymerase chain reaction (RT-PCR) for the presence of ITD mutations in the JM region of the KIT or FMS receptor. None of the 13 human leukemia-lymphoma cell lines or 44 AML primary bone marrow samples express ITDs in either KIT or FMS in the JM region that is involved in FLT3 mutations. The 13 cell lines and 44 AML samples were also examined for the possible co-expression of KIT and/or FMS receptors with their respective ligands, as we have seen for FLT3 and its ligand, FL. This co-expression could contribute to leukemic transformation through autocrine, paracrine, or intracrine activation mechanisms. And 6/13 cell lines and 27/44 primary AML samples exhibit co-expression of the KIT receptor and ligand (SCF) while 10/13 cell lines and 35/44 primary AML samples exhibit co-expression of the FMS receptor and ligand (CSF-1). Therefore, while ITD mutations were not found, the findings of co-expression of KIT and/or FMS with their respective ligands implies these receptors might contribute to leukemogenesis in some patients with AML through autocrine, paracrine, or intracrine interactive stimulation.
KIT和FMS属于III类受体酪氨酸激酶家族成员，在正常造血细胞上表达，在正常造血过程中发挥重要作用。FLT3也是III类受体酪氨酸激酶家族成员，在造血干细胞/祖细胞、自然杀伤细胞和树突状细胞中起重要作用。最近，在急性髓系白血病（AML）和骨髓增生异常综合征（MDS）患者所表达的FLT3受体的近膜（JM）区域发现了内部串联重复（ITD）突变。这些突变导致受体的组成型二聚化和激活，促成白血病转化。KIT和FMS在AML中也经常表达，且与FLT3密切相关。因此，AML患者的KIT和/或FMS基因也可能发生类似的ITD突变。为探究这种可能性，采用逆转录-聚合酶链反应（RT-PCR）检测了13个人类白血病-淋巴瘤细胞系和44例AML患者样本中KIT或FMS受体JM区域ITD突变的存在情况。13个人类白血病-淋巴瘤细胞系或44例AML原发性骨髓样本中，在与FLT3突变相关的JM区域的KIT或FMS中均未表达ITD。还检测了13个细胞系和44例AML样本中KIT和/或FMS受体与其各自配体的共表达情况，正如我们在FLT3及其配体FL中所观察到的那样。这种共表达可能通过自分泌、旁分泌或内分泌激活机制促成白血病转化。13个细胞系中的6个和44例原发性AML样本中的27例表现出KIT受体和配体（SCF）的共表达，而13个细胞系中的10个和44例原发性AML样本中的35例表现出FMS受体和配体（CSF-1）的共表达。因此，虽然未发现ITD突变，但KIT和/或FMS与其各自配体共表达的结果表明，这些受体可能通过自分泌、旁分泌或内分泌相互作用刺激，在一些AML患者的白血病发生过程中发挥作用。
