摘要
目的：
探讨慢性髓系白血病（CML）患者细胞代谢状态以及伊马替尼治疗后敏感和耐药患者代谢的变化差异，综合患者点突变和高密度全基因组单核苷酸多态（SNP）芯片进一步评估细胞代谢与基因的相关性，同时对经典多药耐药基因（MDR1）SNPs分析以探讨CML耐药的机制。
方法：
收集患者的骨髓或外周血标本，分别采用气相飞行时间质谱、逆转录-聚合酶链反应（RT-PCR）联合测序、高密度全基因组SNPs芯片和限制性片段长度多态性-聚合酶链反应（RFLP-PCR）联合测序技术检测代谢组学、ABL1基因点突变、基因型和拷贝数以及MDR1基因的SNPs表达。分析细胞代谢与基因的相关性，伊马替尼耐药的机制。
结果：
1.代谢组学检测
未进行伊马替尼治疗的CML患者代谢组学表型存在尿素循环，三羧酸循环和脂质代谢紊乱，与正常对照组有显著差异；伊马替尼治疗后，达完全细胞遗传学缓解的患者其代谢组学表型明显纠正且趋于正常，但与正常组不重叠，而耐药的CML患者代谢紊乱现象仍存在，与治疗前的代谢表型无显著差异。同时慢性期与急变期的代谢表型差异明显。
2.全基因SNPs芯片
在9例CML标本中（1例伊马替尼敏感CML、4例原发耐药、4例继发耐药）发现44个缺失、2个扩增、7个等位基因杂合性缺失。在CML慢性期无论是伊马替尼敏感或耐药均发现X和Y染色体隐匿缺失。
3. MDR1SNPs与伊马替尼耐药耐药组与非耐药组在C1236T、G2677T/A和C3435T的SNPs表达有显著性差异（p<0.05），且伊马替尼耐药与等位基因T呈剂量相关效应。男性/女性、原发/继发耐药在三个位点的SNPs表达差异无统计学意义(p>0.05)。
4、ABL1激酶区点突变与伊马替尼耐药
1例原发耐药慢性期患者ABL1上第3215号位点发生A>A/C的核苷酸转变；1例继发耐药急变期患者ABL1上第695号位点发生T>C的核苷酸替代，第1006号位点发生T>C的核苷酸替代，第1045号位点发生T>C的核苷酸替代。继发耐药患者ABL1激酶区点突变率为1/6（16.7%），原发耐药患者ABL1激酶区点突变率为1/15（6.7%）；慢性期耐药患者ABL1激酶区点突变率为1/17（5.9%），加速期/急变期患者ABL1激酶区点突变率为1/4（25%）。
结论：
1. CML患者存在代谢紊乱，急变期与慢性期的代谢组学差异与基因的变化密切相关。CML细胞需要更高的能量代谢，需通过碳主链传递上调氨基酸运转，细胞分子合成和信号传导。CML细胞糖酵解增加与其他肿瘤细胞一致。
2.伊马替尼能通过使BCR-ABL阳性细胞代谢从糖酵解转为正常的线粒体代谢而逆转有氧糖酵解现象，造成糖摄入减少，能量增加。
3.伊马替尼敏感CML患者即使已达到细胞遗传学缓解，仍然处于疾病状态。
4.染色体17、9、22缺失和扩增与疾病进展和耐药相关，1号染色体与发病有关，染色体1、11或22的缺失和扩增涉及到CML细胞脂质代谢异常。染色体22缺失涉及糖代谢异常。
5. MDR1C1236T、G2677T/A和C3435T中，等位基因T与伊马替尼耐药相关，体现基因剂量效应。
6.继发耐药患者的突变率高于原发耐药，急变期患者的突变率高于慢性期患者。19例未检测出ABL1激酶区域点突变说明突变仅是导致伊马替尼治疗耐药的因素之一。
Objective
In present study, we integrated metabonomic data with Abl kinase domainmutations and high-density whole genome-wide single nucleotide polymorphism(SNP) array to analyse the metabolic proliles of chronic myeloid leukemia (CML)patients and differentiate their metabolic responses to imatinib. Moreover, weinvestigated the association of SNPs in MDR1(classic multidrug resistance) gene in CMLpatients.
Methods
1. Metabolic compounds in plasma of the59CML patients with imatinib treatmentand18healthy volunteers were detected by gas chromatography-time of flightmass spectrometry (GC-TOFMS), and the correlation between metabolicphenotypes and general characteristics of patients was analyzed.
2. Genomic DNA isolated from cells was subjected to GeneChip Human mappingmicroarray. High-quality genomic DNA was processed in accordance with thegenomic mapping250K NspI protocol and hybridized to250K NspI SNP arraysaccording to the manufacturer’s instructions. Data analysis of deletions,amplifications and loss of heterozygosity (LOH) was carried out using the CNAG(copy number analysis for Affymetrix GeneChips) software with nonmatchedreferences.
3. C1236T、 G2677T/A and C3435T SNPs of MDR1gene were detected byPCR-RFLP (restriction fragment length polymorphism polymerase chain reaction)in52patients with Ph-positive leukemia, who are treated with imatinib.
4. Nested reverse transcription-polymerase chain reaction (RT-PCR) was performedon bone marrow or peripheral blood samples from21resistant CML patients toamplify the ABL1kinase domain，followed by direct sequencing and sequencehomologous analysis．
Results
1. Metabonomics in CML
The significant metabonomic differences, including intermediates of thetricarboxylic acid (TCA) cycle (citrate) and lipid metabolism (cholesterol, HDL,linoleate), between imatinib-untreated CML (UCML) and healthy control (HC)indicate metabolic perturbation in CML patients. After imatinib treatment, themetabolic phenotype of imatinib-sensitive (SCML) was similar to that of HC, butthe two groups did not completely overlap, whereas resistant CML (RCML)patients were not significantly affected. RCML-BC (blastic crisis) patients showeda totally different metabonomic phenotype from that of RCML-CP (chronic phase)patients.
2. High-density SNP array
After exclusion of genomic copy number polymorphisms by comparison ofthe data with recorded copy number polymorphisms in the UCSC Genome Browser(http://genome.ucsc.edu/) databases, a total of44deletions,2duplications, and7regions of loss of heterozygosity (LOH) were identified by SNP array analysis in9CML samples, i.e.,1SCML,4primary RCML and4secondary RCML. Moreover,cryptic deletions on chromosome X and Y were found in patients with CML-CPboth in SCML and RCML.
3. MDR1SNPs
There was no significant difference in MDR1SNPs expression between maleand female patients, no more than the patients who is primary and secondaryresistance to imatinib. But the SNPs expression is statistically linked to theidentification of patients who may or may not respond optimally to imatinib.
4. ABL1kinase domain mutations
We found a single A>A/C nucleotide substitution at position3215of theABL1gene in a primary resistant patient in chronic phase and a single T>Cnucleotide substitution at position695of the ABL1gene, a single T>C nucleotidesubstitution at position1026of the ABL1gene, a single T>C nucleotidesubstitution at position1045of the ABL1gene in a secondary resistant patient inblastic crisis.
The frequency of ABL1mutation in patients with CML secondary resistanceto imatinib is1/6(16.7%), while the primary resistant ones' is1/15(6.7%). Thefrequency of ABL1mutation in chronic phase patients is1/17(5.9%), while theaccelerated phase and blastic crisis ones' is1/4(25%).
Conclusion
1. CML patients have metabolic perturbation. Metabolic variation between BC andCP patients was closely related to genomic alterations. CML cells require higherenergy metabolism. This is achieved through the upregulation of amino acidtransporters, cellular molecule synthesis, and signal transduction by the deliveryof carbon backbones. Increased glycolysis has been consistently observed incancer cells.
2. Imatinib reverses the Warburg effect in BCR–ABL-positive cells by switchingfrom glycolysis to mitochondrial glucose metabolism, resulting in a reduction inglucose uptake and a higher energy state.
3. Patients with imatinib-sensitive CML, even those with a normal karyotype, stillmaintain a diseased status.
4. The deletions and amplifications on chromosomes17,9and22were associatedwith imatinib resistance or disease progression. Chromosome1may be involved inthe initial development of CML，and chromosome1,11or22may lead toabnormal expression of genes which are all involved in cell lipid metabolism.Chromosome22involved in cell sugar transporter SLC2A11.
5. The drug resistance of imatinib correlated with the number of T alleles at locus 1236、3435and2677.
6. Mutation is higher detected in the patients secondary resistance to imatinib thanprimary resistant ones. The frequency of mutation is higher in accelerated phaseand blastic crisis patients than in chronic phase patients.19resistant patientswithout mutation demonstrated that leukemia cells are independent of ABL1kinase activity and rely on other pathways for survivial and proliferation.
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