Jurnal Internasional NCAM1 mendukung resistensi terapi dan fungsi LSC dalam AML
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AML arises from clonal growth. from mutated hematopoietic cells and progenitor cells that exhibit characteristics that are not characteristic such as self-renewal, increased growth, and inability to differentiate into mature offspring. 5 6 The need for more effective therapy is clear, because many patients are refractory to first-line chemotherapy, and recurrence that is resistant to chemotherapy is a major contributor to treatment failure. However, AML is a complex and dynamic malignancy that can arise from a variety of combinations of genetic mutations that are rare where patients often display several clones that coexist mutually diverse. 6 7 Despite attempts to target certain genes that more often mutate (such as FLT3 or IDH2 ) have shown clinical efficacy, strategies that target molecules or uncharted pathways that are explicitly expressed / activated apart from highly desirable genetic subtypes.
NCAM1 expression is mostly related to healthy neural networks and lymphocytic lineage cells such as NK cells, but has also been observed in many solid cancers and haematological tumor. In AML, its expression is found in 15% to 20% of patients analyzed, especially at t (8; 21) and acute promyelocytic leukemia, where it identifies subgroups of patients with a more unfavorable prognosis, extramedullary leukemia, and shorter remissions. 2 19 – 4 However, before the research put forward on this issue by Sasca et al, the molecular mechanisms underlying this association were not investigated.
Sasca et al show that NCAM1 heterogeneous expressions in various AML genetic subtypes, with the exception of AML-karyotype complexes (CK-AML) as well as AMLs containing 11q23 or t (8; 21) rearrangements, which display significantly higher NCAM1 levels relative to other genetic subtypes. 1 Sasca et al also presents data that the NCAM1 expression is driven by several transcription factors, such as MEIS1, MEF2C, and STAT1, but does so in the cell context (see figure). 1  To investigate the functional role of NCAM1 in human AML cell biology, Sasca et al used an inducible shRNA system and observed that inhibition of NCAM1 expression selectively inhibited NCAM1-positive growth (NCAM1 + ) Human AML cells, both in vitro and in vivo. In particular, Sasca et al. Also showed that inhibition of NCAM1 made NCAM1 + AML cells more sensitive to first-line chemotherapy AML Fig-C in vivo, and the NCAM1 expression applied partially protected NCAM1-negative (NCAM1 ] – ) AML cells from Ara-C or daunorubicin treatment in vitro.
Given that LSC is considered the architect of disease removal and chemotherapy, 8 Sasca et al explores the role NCAM1 in LSC biology in the AML mouse model is driven by rearrangement 11q23, MLL-AF9. Comparison of various populations of stem cells and murine malignant and healthy progenitor cells revealed that LSCs expressing MLL-AF9 display a much higher level of Ncam1 compared to all other populations. Importantly, Sasca et al. Also showed that the removal of Ncam1 significantly extended the time of occurrence of the disease and drastically reduced the frequency of LSC in this model.
Using a combination of phosphonatromomic and RNA-seq analysis, Sasca et al found that inhibition of NCAM1 reduces several signal transduction pathways, including MAPK signaling, and transcription programs related to glucose metabolism and hypoxia. Utilizing this observation, they also show evidence that NCAM1 AML cells were significantly more sensitive to the MAPK inhibitors compared to NCAM1 – AML cell lines, and that the trametinib MAPK inhibitors synergistically worked with Ara-C for removing NCAM1 + AML cell lines.
Data presented by Sasca et al have some potentially clinically relevant consequences. First, the data presented that the NCAM1 pathway supports the survival of leukemic cells makes it an attractive therapeutic target, especially for CAM-AML that expresses NCAM1 and 11q23 rearranging AML, which is well known to be associated with a poor response to current therapy. However, given that NCAM1 is widely expressed in the nervous system and other hematopoietic populations, it will be very important for future research to focus on identifying and targeting downstream molecular events that NCAM1 is involved in uniquely supporting AML. Second, NCAM1 can represent biomarkers to guide treatment decisions. For example, clinical trials evaluating MAPK inhibitors in AML mainly focus on patients expressing RAS mutations; However, this study produces limited to moderate efficacy. 9 10 The results presented by Sasca et al indicate that NCAM1 can be a biomarker that is thought to identify patients who might benefit from MAPK-based therapy inhibitors, especially in combination with Ara-C. Third, the observation that NCAM1 marks and supports LSC functionally in AML mouse models may be relevant in NCAM1 + AML humans. For example, if NCAM1 is expressed in the LSC / preleukemia clone population in human AML, NCAM1 can function as a marker to identify or possibly therapeutically target this population. Therefore, in the future it will be important to assess NCAM1 expression in all leukemia and preleukemia clones present in patient samples given to understand the clinical potential of this surface protein in AML.