| Objective：Most AML cannot be cured since eventual relapse is occasionally unavoidable. It isthus imperative to monitor MRD during CR to track impending relapse. In MDS, patientswith positive ALIP in BM sections indicate shorter-term to transform to leukemia thanthose with negative ALIP cluster. In AML, we also found ALIP-like cluster during CR. Inthis paper, we will investigate the relationship between ALIP during CR and relapse risk,and assess it in relapse heralding as a prognostic factor. Meanwhile, we will exploitpathological criteria for diagnosis of early relapse. Furthermore, two potential mechanismof ALIP-like cluster forming will be probed. One is fibre-anchored and the other isdifferentiation and migration of LSC that located in endostreuml. Lastly, targeted therapybased on ALIP-like cluster is expected to prevent early relapse.Methods：(1)47patients with AML during CR were retrospectively studied. Patients weredivided into pre-relapsed group and non-relapsed group according to relapse or not duringour follow-up. Bone marrow biopsies were performed and concentration of ALIP-likecluster is calculated before every cycle of chemotherapy. Statistics analysis is used tocompare the different concentrations of ALIP-like cluster between the two groups and theireffects on RFS and OS.(2)RFD was quantify-calculated in leukemogenesis and during follow-up afterchemotherapy and it was compared between the two groups. Additionally, to investigate the relationship between ALIP-like cluster and RFD, the concentration of ALIP-like clusterwas simultaneously calculated while RFD was investigated.(3)To address the underlying mechanism of ALIP-like cluster forming, distances ofsingle, double and clustered precursors to trabecular bone during trabecular bone weredetected by computer image process; To examine whether ALIP are of myeloid lineage,immunostain assay was performed; Mouse model with PML/RARα carried myeloid cellstransplant was used to investigate the underlying mechanism of ALIP-like cluster forming,and PML/RARα mRNA levels were detected during the forming of ALIP-like cluster.Results：(1)The concentrations of ALIP-like cluster in pre-relapse group and non-relapse groupare (3.46±2.71)/mm2and (2.09±2.10)/mm2, it is significant higher in pre-relapse group(p<0.05). While analyze the relationship between ALIP-like cluster and relapse, ROCcurse is used and AUC is available with0.67, and the threshold value of ALIP-like clusterfor relapse is determined as4clusters/mm2. To testify the sensitivity in relapse heralding,cases were divided into two groups according to the value and RFS and OS were comparedbetween the two groups. Cases with>4/mm2of clusters indicated months of relapse freeand it was much shorter than cases with≤4/mm2of clusters which with months(p<0.05).(2)In pre-relapse group, the RFD is(2.76%±1.50%) before chemotherapy, it wassignificant higher than that in non-relapse group (1.34%±0.51%) with p<0.05. ROCanalysis showed that RFD more than1.68%indicated higher frequency of relapse and poorRFS (p<0.05), Concentration of ALIP-like cluster carried no relationship with RFD in bothbefore and after chemotherapy.(3)IHC showed that ALIP like clusters are MPO positive, CD34and CD117positiveor both negative In mice model, it observed that single, double and clustered precursorsfarther away from endostreum step by step, on day5, ALIP are easily observed and on thetime-point PML/RARα mRNA transcript was detected in trace level;. VLA-4、VEGF、VEGFR-1、VEGFR-2、 CXCR4were expressed in higher level in recipient mice than those in healthy counterparts.Conclusion：(1) ALIP-like cluster is a prognostic factor, and ALIP-like cluster>4/mm2is the cutoffto evaluate poor prognosis in RFS and OS, timely interventions are necessary forpreventing early relapse.(2) There was no relationship between density of ALIP-like cluster and fibre, itsuggested that the forming of ALIP-like cluster is independent of anchoring fibre. However,fibro-genesis in BM is another prognostic factor.(3) ALIP-like clusters during CR of AML patients may be the daughter cells thatdifferentiate and migrate from LSC harboring in endotrium during chemotherapy. It maybe the histological manifestation for early relapse. |
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