Melphalan

Landmark approval is based on results from the Phase 3 AQUILA study, showing fixed-duration treatment with daratumumab significantly reduced the risk of progression to active multiple myeloma or death by 51 percent compared to active monitoring 1 This milestone marks a critical advance in early intervention for multiple myeloma as the first authorised treatment, offering a new treatment paradigm for patients with high-risk smouldering disease 2 BEERSE, Belgium I July 23, 2025 I Janssen-Cilag International NV, a Johnson & Johnson company, today announced that the European Commission (EC) has approved a new indication for DARZALEX ® (daratumumab) subcutaneous (SC) formulation as monotherapy for the treatment of adult patients with smouldering multiple myeloma (SMM) at high-risk of developing multiple myeloma. 3 SMM is an asymptomatic intermediate disease state of multiple myeloma where abnormal cells can be detected in the bone marrow. 2,4,5 “Until now, the absence of approved therapies for high-risk smouldering multiple myeloma has left clinicians with limited options beyond observation, despite evidence that 50 percent of this patient population progress to active multiple myeloma within two years,” said Professor Meletios A. Dimopoulos, M.D., National and Kapodistrian University of Athens School of Medicine.* “The approval of daratumumab offers the potential to change this trajectory. By intervening earlier in the disease course, we have a meaningful opportunity to delay or prevent progression to symptomatic disease, reduce irreversible end-organ damage and extend the window of improved patient outcomes.” “This new indication for daratumumab SC is an exciting step forward in addressing a long-standing unmet clinical need for those diagnosed with high-risk smouldering multiple myeloma and is the first time a treatment has been approved for this patient population,” said Ester in ’t Groen, EMEA Therapeutic Area Head Haematology, Johnson & Johnson Innovative Medicine. “It means that eligible patients no longer have to live with the uncertainty or fear of waiting for progression to occur without active treatment, instead having the option to intercept the disease with therapeutic intervention.” The Phase 3 AQUILA study ( NCT03301220 ) is the largest randomised study of a well-defined high-risk SMM population, evaluating the efficacy and safety of fixed-duration, monotherapy daratumumab SC (n=194) compared with active monitoring (n=196). 1 At a median follow-up of 65.2 months (range, 0-76.6), patients who received daratumumab SC showed statistically significant improved progression-free survival (PFS; defined as progression to active multiple myeloma, as assessed according to the International Myeloma Working Group diagnostic criteria for multiple myeloma [SLiM-CRAB], or death) compared to patients who underwent active monitoring; 63.1 percent in the daratumumab arm versus 40.8 percent in the active monitoring arm remained alive and progression-free at 60 months (hazard ratio [HR], 0.49; 95 percent confidence interval [CI], 0.36-0.67; p <0.001). 1 Among patients who were retrospectively categorised as having high-risk SMM, per the current Mayo 2018 criteria (20/2/20), median PFS was not reached in the daratumumab arm and was 22.1 months in the active monitoring arm (HR, 0.36; 95 percent CI, 0.23-0.58). 1 Overall survival was also extended with daratumumab SC, with 5-year survival rates of 93.0 percent vs 86.9 percent for active monitoring (HR, 0.52; 95 percent CI, 0.27-0.98). 1 Additionally, patients who received daratumumab SC saw a higher overall response rate of 63.4 percent compared to 2.0 percent with active monitoring ( p <0.001). 1 Median time to first-line multiple myeloma treatment was not reached for patients receiving daratumumab SC compared to 50.2 months with active monitoring (HR, 0.46; 95 percent CI, 0.33-0.62; nominal p <0.0001). 1,6 Daratumumab demonstrated a safety profile consistent with previous studies of daratumumab in other indications, with a low rate of treatment discontinuation due to treatment-emergent adverse events (TEAEs). 1 Grade 3/4 TEAEs occurred in 40.4 percent of patients treated with daratumumab SC and 30.1 percent of patients actively monitored. 1 The most common (≥5 percent in either group) Grade 3/4 TEAE was hypertension (5.7 percent vs 4.6 percent, respectively). 1 The frequency of TEAEs leading to discontinuation of daratumumab SC was low (5.7 percent), as was the incidence of fatal TEAEs in both groups (1.0 percent vs 2.0 percent, respectively). 1 “Until now, there have been no approved treatment options for patients diagnosed with high-risk smouldering multiple myeloma,” said Jordan Schecter, M.D., Vice President, Disease Area Leader, Multiple Myeloma, Johnson & Johnson Innovative Medicine. “With today’s approval, Johnson & Johnson has an innovative therapy for every stage of the disease. We can now offer physicians and patients the option to treat with daratumumab earlier, significantly delaying progression and the need for more intensive, continuous therapy, as well as extending overall survival. We remain steadfast in our mission to get in front of cancer.” About the AQUILA Study AQUILA ( NCT03301220 ) is a randomised, multicentre Phase 3 study investigating daratumumab SC versus active monitoring in patients (n=390) with high-risk smouldering multiple myeloma (SMM). 7 The primary endpoint is progression-free survival and secondary endpoints include time to progression, overall response rate and overall survival. 7 Patients in the study were diagnosed with SMM in the last five years and were excluded if they had prior exposure to approved or investigational treatments for SMM or multiple myeloma. 7 About Smouldering Multiple Myeloma SMM is an asymptomatic intermediate disease state of multiple myeloma where abnormal cells can be detected in the bone marrow. 2,8 Patients living with SMM tend not to show signs or symptoms typically associated with active myeloma, such as bone pain, bone fractures, kidney problems, or anaemia, however as abnormal plasma cells are present, organ damage may begin and progress asymptomatically. 1,9 Approximately 15 percent of all cases of newly diagnosed multiple myeloma are classified as SMM, and half of those diagnosed with high-risk SMM are estimated to progress to active multiple myeloma within two years. 10 About Multiple Myeloma Multiple myeloma is currently an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow. 11,12 In multiple myeloma, these malignant plasma cells continue to proliferate, accumulating in the body and crowding out normal blood cells, as well as often causing bone destruction and other serious complications. 11,12 In the European Union, it is estimated that more than 35,000 people were diagnosed with multiple myeloma in 2022, and more than 22,700 patients died. 13 Patients living with multiple myeloma experience relapses which become more frequent with each line of therapy while remissions become progressively shorter. 14,15,16 Whilst some patients with multiple myeloma initially have no symptoms, others can have common signs and symptoms of the disease, which can include bone fracture or pain, low red blood cell counts, fatigue, high calcium levels, infections, or kidney damage. 17 About Daratumumab and Daratumumab SC Johnson & Johnson is committed to exploring the potential of daratumumab for patients with multiple myeloma across the spectrum of the disease. In August 2012 , Janssen Biotech, Inc., a Johnson & Johnson company, and Genmab A/S entered a worldwide agreement, which granted Johnson & Johnson an exclusive licence to develop, manufacture and commercialise daratumumab. Since launch, daratumumab has become a foundational therapy in the treatment of multiple myeloma, having been used in the treatment of more than 618,000 patients worldwide. 18 Daratumumab is the only CD38-directed antibody approved to be given subcutaneously to treat patients with multiple myeloma. 19 Daratumumab SC is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE ® drug delivery technology. 19 CD38 is a surface protein that is present in high numbers on multiple myeloma cells, regardless of the stage of disease. 19 Daratumumab binds to CD38 and inhibits tumour cell growth causing myeloma cell death. 19 Daratumumab may also have an effect on normal cells. 19 Data across ten Phase 3 clinical trials, in both the frontline and relapsed settings, have shown that daratumumab-based regimens resulted in significant improvement in progression-free survival and/or overall survival. 20,21,22,23,24,25,26,27,28 For further information on daratumumab, please see the Summary of Product Characteristics at: https://ec.europa.eu/health/documents/community-register/html/h1101.htm . About Johnson & Johnson At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow. and profoundly impact health for humanity. Learn more at www.innovativemedicine.jnj.com/emea . Follow us at www.linkedin.com/company/jnj-innovative-medicine-emea . Janssen-Cilag International NV, Janssen Pharmaceutica NV, Janssen-Cilag Limited, Janssen Biotech, Inc. and Janssen Research & Development, LLC are Johnson & Johnson companies. *Professor Meletios A. Dimopoulos, M.D., National and Kapodistrian University of Athens School of Medicine, has provided consulting, advisory, and speaking services to Johnson & Johnson; he has not been paid for any media work. 1 Dimopoulos MA, et al. Phase 3 Randomized Study of Daratumumab Monotherapy versus Active Monitoring in Patients with High-risk Smoldering Multiple Myeloma: Primary Results of the AQUILA study. Oral presentation. American Society of Hematology (ASH) Annual Meeting; December 7-10, 2024. 2 Myeloma UK. Smouldering Myeloma. Available at: https://www.myeloma.org.uk/wp-content/uploads/2023/04/Myeloma-UK-Smouldering-Myeloma-Infosheet.pdf . Last accessed: July 2025. 3 European Medicines Agency. DARZALEX (daratumumab) Summary of Product Characteristics. July 2025. 4 Oben B, et al. Whole-Genome Sequencing Reveals Progressive Versus Stable Myeloma Precursor Conditions as Two Distinct Entities. Nature Communications. 2021; 12(1861). 5 Maura F, et al. Targeting the Tumor and The Immune System in Smoldering Multiple Myeloma. The New England Journal of Medicine. 2025;392:1858-1860. 6 Dimopoulos MA, et al. Phase 3 Randomized Study of Daratumumab Monotherapy Versus Active Monitoring in Patients With High-risk Smoldering Multiple Myeloma: Primary Results of the AQUILA Study. Abstract #773. American Society of Hematology (ASH) Annual Meeting; December 7-10, 2024. 7 ClinicalTrials.Gov. A Study of Subcutaneous Daratumumab Versus Active Monitoring in Participants With High-Risk Smoldering Multiple Myeloma. Available at: https://clinicaltrials.gov/study/NCT03301220 . Last accessed: July 2025. 8 WebMD. Smoldering Multiple Myeloma. Available at: https://www.webmd.com/cancer/multiple-myeloma/smoldering-multiple-myeloma . Last accessed: July 2025 9 American Cancer Society. About Multiple Myeloma. Available at: https://www.cancer.org/cancer/types/multiple-myeloma/about/what-is-multiple-myeloma.html . Last accessed: July 2025. 10 Rajkumar SV, et al. Smoldering Multiple Myeloma Current Treatment Algorithms. Blood Cancer J. 2022;12(9):129. 11 Abdi J, et al. Drug Resistance in Multiple Myeloma: Latest Findings on Molecular Mechanisms. Oncotarget. 2013;4(12):2186-2207. 12 American Society of Clinical Oncology. Multiple Myeloma: Introduction. Available at: https://www.cancer.org/cancer/types/multiple-myeloma/if-you-have-multiple-myeloma . Last accessed: July 2025. 13 ECIS – European Cancer Information System. Estimates of Cancer Incidence and Mortality in 2022, by Country. Multiple Myeloma. Available at: https://ecis.jrc.ec.europa.eu/explorer.php?$0-0$1-All$2-All$4-1,2$3-51$6-0,85$5-2022,2022$7-7$CEstByCountry$X0_8-3$X0_19-AE27$X0_20-No$CEstBySexByCountry$X1_8-3$X1_19-AE27$X1_-1-1$CEstByIndiByCountry$X2_8-3$X2_19-AE27$X2_20-No$CEstRelative$X3_8-3$X3_9-AE27$X3_19-AE27$CEstByCountryTable$X4_19-AE27 . Last accessed: July 2025. 14 Bhatt P, et al. Relapsed/Refractory Multiple Myeloma: A Review of Available Therapies and Clinical Scenarios Encountered in Myeloma Relapse. Curr Oncol. 2023;30(2):2322-2347. 15 Hernández-Rivas JÁ, et al. The Changing Landscape of Relapsed and/or Refractory Multiple Myeloma (MM): Fundamentals and Controversies. Biomark Res. 2022;10(1):1-23. 16 Gavriatopoulou M, et al. Metabolic Disorders in Multiple Myeloma. Int J Mol Sci. 2021;22(21):11430. 17 American Cancer Society. Multiple Myeloma: Early Detection, Diagnosis and Staging. Available at: https://www.cancer.org/content/dam/CRC/PDF/Public/8740.00.pdf. Last accessed: July 2025. 18 J&J Data on File (RF-452129). Number of Patients Treated with DARZALEX Worldwide as of December 2024. 19 Janssen EMEA. European Commission Grants Marketing Authorisation for DARZALEX ® (Daratumumab) Subcutaneous Formulation for All Currently Approved Daratumumab Intravenous Formulation Indications. Available at: http://www.businesswire.com/news/home/20200604005487/en/European-Commission-GrantsMarketingAuthorisation-for-DARZALEX%C2%AE%E2%96%BC-daratumumab-SubcutaneousFormulation-for-all-CurrentlyApproved-Daratumumab-Intravenous-Formulation-Indications . Last accessed: July 2025. 20 Moreau P, et al. Bortezomib, Thalidomide, and Dexamethasone With or Without Daratumumab Before and After Autologous Stem-Cell Transplantation for Newly Diagnosed Multiple Myeloma (CASSIOPEIA): A Randomised, Open-label, Phase 3 Study. Lancet. 2019;394(10192):29-38. 21 Facon T, et al. MAIA Trial Investigators. Daratumumab Plus Lenalidomide and Dexamethasone for Untreated Myeloma. New England Journal of Medicine. 2019;380(22):2104-2115. 22 Mateos MV, et al. Overall Survival with Daratumumab, Bortezomib, Melphalan, and Prednisone in Newly Diagnosed Multiple Myeloma (ALCYONE): A Randomised, Open-label, Phase 3 Trial. The Lancet. 2020;395:132-141. 23 Dimopoulos MA, et al. APOLLO Trial Investigators. Daratumumab Plus Pomalidomide and Dexamethasone Versus Pomalidomide and Dexamethasone Alone in Previously Treated Multiple Myeloma (APOLLO): An Open-label, Randomised, Phase 3 Trial. Lancet Oncol. 2021;22(6):801-812. 24 Palladini G, et al. Daratumumab Plus CyBorD for Patients with Newly Diagnosed AL Amyloidosis: Safety Run-in Results of ANDROMEDA. Blood 2020;2;136(1):71-80. 25 Chari A, et al. Daratumumab Plus Pomalidomide and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma. Blood. 2017;130(8):974-981. 26 Bahlis NJ, et al. Daratumumab Plus Lenalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Extended Follow-up of POLLUX, A Randomized, Open-label, Phase 3 study. Leukemia. 2020;34(7):1875-1884. 27 Mateos MV, et al. Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Patients with Previously Treated Multiple Myeloma: Three-Year Follow-up of CASTOR. Clin Lymphoma Myeloma Leuk. 2020;20(8):509-518. 28 Usmani S Z, et al. Daratumumab + Bortezomib/Lenalidomide/Dexamethasone in Patients with Transplant-Ineligible or Transplant-Deferred Newly Diagnosed Multiple Myeloma: Results of the Phase 3 CEPHEUS Study. Oral Presentation. 21 st International Myeloma Society (IMS) Annual Meeting. September 25 – 28, 2024. SOURCE: Johnson & Johnson

引言化学疗法(Chemotherapy)，也就是我们常说的“化疗”，无疑是人类手中最强有力的武器之一。它像一位无畏的战士，深入敌后，精准打击快速分裂的癌细胞，为无数患者带来了生命的曙光。然而，正如所有威力巨大的武器都具有两面性，化疗这把锋利的“双刃剑”，在斩妖除魔的同时，其挥舞的剑风也可能误伤友军——我们体内健康的细胞。其中，最令人担忧的“误伤”之一，便是在化疗的硝烟散去数年后，一种被称为“治疗相关性髓系肿瘤”(Therapy-related Myeloid Neoplasms, t-MNs)的新型癌症悄然崛起。这就像是我们在扑灭一场大火后，却发现火场的余烬中，竟埋藏着一颗新的“定时炸弹”。这颗炸弹是如何被埋下的？化疗究竟对我们体内负责制造所有血细胞的“种子”——造血干细胞(Hematopoietic Stem Cells, HSCs)——做了什么？这些细胞的命运又是如何被改写，最终从“良民”演变为“叛军”的？长期以来，这些问题一直笼罩在迷雾之中。7月1日，一篇发表于《Nature Genetics》的研究“Clonal evolution of hematopoietic stem cells after autologous stem cell transplantation”，为我们揭开了这层神秘面纱。研究人员以前所未有的精度，深入“审问”了那些经历过化疗洗礼的造血干细胞，绘制出了一幅关于它们在压力下演化、竞争乃至最终“黑化”的惊人图景。这不仅是一次对生命奥秘的探索，更可能为未来预防和拦截这种致命的“二次打击”提供了关键线索。深入虎穴：如何“审问”经历过化疗的造血干细胞？要理解这场发生在微观世界里的“权力的游戏”，要先认识游戏的主角——造血干细胞和祖细胞(Hematopoietic Stem and Progenitor Cells, HSPCs)。你可以将它们想象成我们血液王国的“始祖”，体内所有的红细胞、白细胞、血小板，都是由这些“始-祖-细-胞”经过不断分化和增殖而来。它们居住在我们的骨髓深处，默默地维持着整个血液系统的平衡与更新。这项研究的核心，就是去探究化疗这场“天灾”过后，这些“始祖细胞”的内在世界发生了怎样的变化。为此，研究人员进行了一项精密的“犯罪现场调查”。他们招募了10位曾因多发性骨髓瘤(Multiple Myeloma, MM)接受过化疗和自体干细胞移植(Autologous Stem Cell Transplantation, ASCT)的患者，同时，邀请了6位健康的捐赠者作为对照组。这个设计非常关键，通过对比“经历过战火”的细胞和“生活在和平年代”的细胞，我们才能真正看清化疗留下的烙印。研究人员采用了“单细胞集落全基因组测序”(single-cell colony whole-genome sequencing)的技术。这个名字听起来很复杂，但原理却很巧妙：1. “单细胞”隔离：他们从患者的外周血中，分离出单个的HSPC。2. “集落”培养：将这个孤独的细胞放入特制的培养基中，让它自由生长，分裂增殖，形成一个由成千上万个细胞组成的“克隆家族”(colony)。这个家族里的所有成员，理论上都拥有与最初那个“始祖细胞”完全相同的基因组。3. “全基因组测序”：最后，研究人员提取这个“克隆家族”的全部DNA，进行全基因组测序。这个方法的威力在于，它能精确地揭示出最初那个“始祖细胞”在其一生中所积累的所有基因突变。这就像是为每一个“始祖细胞”撰写了一部独一无二的“生命史书”。通过对总共1276个这样的细胞“家族”进行测序分析，研究人员得以用前所未有的分辨率，观察化疗对单个干细胞基因组的直接冲击，以及对整个干细胞群体生态格局的深远影响。作案“凶器”大揭秘：不同化疗药物留下的独特“犯罪特征”我们每个人的细胞，在其生命历程中，都会因为细胞分裂时的复制错误或环境因素，不断地积累基因突变。这个过程就像一块走得非常准的“分子钟”(molecular clock)。此前的研究已经证实，正常情况下，一个造血干细胞每年会稳定地积累大约16到25个新的单核苷酸突变(Single-Nucleotide Variants, SNVs)。在这项研究中，研究人员通过分析6位健康捐赠者的样本，也得出了一个非常一致的数字：每年17.2个突变。这为他们评估化疗的影响，提供了一个坚实的基准。当研究人员将目光投向那10位接受过化疗的患者时，一个戏剧性的发现出现了。在大多数（8位）患者体内，HSPC的突变总数与同龄健康人相比，并没有显著增加。这似乎在说，大部分化疗药物并没有直接在干细胞的“生命史书”上留下大量“涂鸦”。然而，有两位患者（编号为PID0003和PID0004）的情况却截然不同。他们体内的HSPC，其突变数量几乎是同龄人预期值的两倍甚至更高！是什么导致了这种惊人的差异？研究人员立刻追溯了这两位患者的用药史。答案很快浮出水面：这两位患者都曾接受过一种名为马法兰(Melphalan)的化疗药物治疗。这还不是全部。研究人员进一步分析了这些突变的“模式”——也就是所谓的“突变印记”(mutational signature)。不同的致癌因素（如紫外线、烟草）会在DNA上留下独特的突变模式，就像不同罪犯会留下独特的“犯罪特征”。在这两位患者体内，研究人员发现了一种此前未在正常衰老中见过的、非常独特的突变印记，他们将其命名为SBS-C。通过与已知的突变印记数据库进行比对，他们发现，SBS-C与先前在多发性骨髓瘤细胞中发现的、被认为是马法兰诱导的突变印记(SBS-MM1)，有着高达90%的余弦相似度。更具说服力的是，通过构建这些细胞的“家族谱系”（系统发育树），研究人员发现，SBS-C这种突变印记，只出现在这两位患者生命历程的后期，也就是在他们接受马法兰治疗之后的时间点上。这无疑是“人赃并获”的铁证，明确地将马法兰与HSPC基因组的直接损伤联系在了一起。更有趣的是，研究中还有几位患者接受过另一种同属烷化剂的化疗药——环磷酰胺(cyclophosphamide)——的治疗。但出人意料的是，在这些患者的HSPC中，研究人员并未观察到突变数量的增加，也没有发现特殊的突变印记。同为“兄弟”，为何表现如此不同？论文给出了一个可能的解释：造血干细胞内部含有一种叫做“醛脱氢酶”的物质，它能够巧妙地将环磷酰胺分解为无活性的形式，从而避免了DNA损伤。而马法兰则能绕过这道防线，直接在HSPC的DNA上形成加合物，造成损伤。这一发现揭示了一个至关重要的事实：化疗药物对我们干细胞基因组的影响是高度特异性的。并非所有化疗都是“无差别轰炸”，不同的药物，其“作案手法”和留下的“犯罪特征”可能天差地别。血细胞江湖的“权力的游戏”：化疗如何加速“改朝换代”？除了直接在DNA上留下伤疤，化疗还以一种更隐蔽、但影响更深远的方式，重塑了我们体内的血细胞江湖——它彻底改变了“权力格局”。在一个健康的年轻人体内，造血干细胞的世界是“多元化”的。成千上万个不同的HSPC克隆（即来自不同“始祖”的细胞家族）共同存在，百花齐放，维持着血液系统的稳健。然而，随着年龄的增长，一些携带了“优势”突变(driver mutations)的克隆会开始悄悄扩张，挤占其他克隆的生存空间，导致整个系统的多样性下降。这个过程被称为“克隆性造血”(Clonal Hematopoiesis, CH)。当多样性极度降低，由少数几个“超级克隆”主导全局时，就形成了所谓的“寡克隆”格局(oligoclonality)。这在老年人中非常普遍，也是血液肿瘤发生的重要前奏。现在，让我们回到化疗后的患者身上。研究人员通过分析系统发育树发现，这些患者的HSPC群体展现出一种惊人的“早衰”现象。在许多患者体内，都出现了几个异常庞大的克隆，占据了HSPC群体的半壁江山，形成了明显的寡克隆格局。为了量化这一现象，研究人员计算了每个样本的“辛普森均匀度指数”(Simpson's evenness index)，这个指数越高，代表克隆多样性越好。结果令人震惊：化疗后患者的干细胞克隆多样性，显著低于同龄的健康对照组，其水平竟然与75岁以上高龄老年人的水平相当！换句话说，一场化疗，让这些四五十岁患者的造血系统，仿佛瞬间“衰老”了二三十年。这背后的机制，堪称一场微观世界的“物竞天择，适者生存”。化疗就像一场突如其来的严酷寒冬，大多数正常的HSPC因为无法耐受其毒性而凋亡，造成了剧烈的“种群瓶颈”(population bottleneck)。然而，在灾难降临之前，群体中总有那么一些细胞，碰巧获得了一些特殊的基因突变。这些突变，在平时可能毫无用处，甚至有些“怪异”，但在化疗带来的极端环境下，却赋予了它们超强的生存能力。研究人员发现，在这些幸存并急剧扩张的“超级克隆”中，携带TP53和PPM1D基因突变的细胞占据了绝对优势。这两个基因都是DNA损伤应答(DNA-damage response, DDR)通路中的关键成员，可以被看作是细胞内的“首席工程师”，负责在DNA受损时启动修复程序。当化疗药物（尤其是损伤DNA的药物）来袭时，那些“首席工程师”出了问题的细胞（即TP53或PPM1D突变），反而因为无法正常启动细胞凋亡程序而得以“苟活”，并获得了巨大的选择优势。研究人员甚至观察到了“趋同演化”(convergent evolution)的奇特现象。在同一位患者体内，他们常常能发现多个（有时多达六个）携带不同TP53或PPM1D突变的独立克隆，在“平行”地扩张。这就像是在一场大瘟疫过后，幸存下来的村落，虽然彼此隔绝，但都独立地演化出了相似的抗病能力。这强有力地证明了，化疗施加的选择压力是多么巨大和明确，它在无情地筛选着那些最能抵抗死亡的“天选之子”。从“乱世枭雄”到“癌症君主”：追踪那颗最终“黑化”的干细胞至此，我们已经看到，化疗在HSPC群体中筛选出了一批携带高风险突变的“乱世枭雄”。它们在化疗后的废墟上迅速崛起，各自为政，形成了寡头垄断的局面。但这还不是故事的终点。真正的危险在于，这些“枭雄”中的某一个，可能会在未来的某一天，积累更多的突变，最终“黄袍加身”，演变为真正的“癌症君主”——也就是t-MN。那么，最终是哪个“枭雄”登上了王座？它的“登基之路”又是怎样的？这正是这项研究最令人拍案叫绝的部分。由于研究人员同时拥有了患者在t-MN确诊时的癌细胞样本，以及多年前移植前采集的HSPC“快照”，他们得以进行一场跨越时空的“亲子鉴定”。通过比对癌细胞的基因组和早期HSPC克隆的基因组，他们可以精确地追溯t-MN的克隆起源。结果再次带来了震撼性的发现。在9位最终发展为t-MN的患者中，研究人员竟然在其中5位（占比56%）的早期HSPC样本中，成功找到了后来癌细胞的“最近共同祖先”(Most Recent Common Ancestor, MRCA)！以患者PID0002为例，这位患者在移植一年后被诊断为t-MDS（一种t-MN）。研究人员在他的早期HSPC样本中，发现了一个非常显赫的克隆，这个克隆已经携带了TET2基因的突变。更重要的是，这个克隆的某个“子孙”细胞，又进一步获得了TP53基因的突变，甚至还发生了17号染色体短臂的杂合性丢失(Loss of Heterozygosity, LOH)，这相当于让TP53这个重要的“抑癌将军”彻底“双臂被斩”，功能尽失。而当研究人员分析这位患者的t-MDS癌细胞时，发现其MRCA正是这个同时携带TET2突变、TP53突变和17p LOH的细胞。最终的癌变，只是在这个基础上，又增加了5号和7号染色体丢失等几次“致命一击”。这条清晰的演化路径，从一个普通的克隆性造血，到携带高风险突变的“优势克隆”，再到获得双等位基因TP53失活的“准癌克隆”，最终演变为真正的癌症，被研究人员完整地描绘了出来。这表明，t-MN的发生并非一蹴而就，而是一个由多个基因事件逐步累积、并由化疗驱动选择的、漫长的演化过程。研究人员还提出了一个有趣的假说，即t-MN的起源可能存在两种模式。大多数t-MN可能起源于那些被采集出来、经历了化疗筛选、最终又被移植回患者体内的外周血干细胞（即模型1）。但还有一种可能，少数t-MN可能起源于那些“藏”在骨髓深处、没有被动员采集、但却结结实实地承受了移植前大剂量“清髓”化疗（如大剂量马法兰）冲击的“留守”干细胞（即模型2）。这一假说也得到了部分数据的支持，为理解t-MN的复杂起源提供了新的视角。站在十字路口：我们该如何驾驭这把锋利的“双刃剑”？这项里程碑式的研究，如同一盏明亮的探照灯，照亮了化疗后血细胞世界那片幽暗而复杂的“无人区”。它以确凿的数据和严谨的逻辑，向我们揭示了化疗对正常造血干细胞的双重深远影响：其一，是直接的基因“雕刻”效应。像马法兰这样的特定化疗药物，可以直接在HSPC的基因组上留下永久的、可识别的突变伤疤，甚至可能直接“制造”出一些致癌的驱动突变。其二，是间接的生态“重塑”效应。这是更普遍、影响更广的影响。化疗通过创造一个极端的生存环境，强力筛选出那些碰巧携带了抗性突变（尤其是TP53和PPM1D突变）的HSPC克隆，导致整个造血系统的克隆多样性急剧下降，进入一种“加速衰老”的状态。最终，这两股力量交织在一起。在被化疗重塑的、由少数“枭雄”主导的寡克隆格局中，某一个高风险克隆，在获得了后续的关键突变（如TP53的双等位基因失活）后，便能脱颖而出，完成从“枭雄”到“君主”的转变，最终导致t-MN的发生。这些发现的临床意义不言而喻。它告诉我们，t-MN的风险并非虚无缥缈、无法预测。通过在化疗后对患者的血液样本进行深度测序，监测那些高风险克隆（如携带TP53突变的克隆）的动态变化，特别是其等位基因状态（是否发生LOH），我们或许能够像天气预报一样，提前预警t-MN的“来袭”。更进一步，这为“早期拦截”策略提供了理论基础。既然我们知道TP53突变的细胞在癌变前大多是基因组稳定的，那么在它们积累更多染色体异常、变得“无可救药”之前，开发针对性疗法将其清除，或许能从根本上阻止t-MN的发生。当然，这项研究并非要我们因噎废食，放弃化疗。恰恰相反，它让我们能更深刻地理解这把“双刃剑”的属性，从而更智慧地去驾驭它。未来的癌症治疗，将不再仅仅是关注如何杀死癌细胞，更要关注如何保护和维持我们体内正常干细胞的健康生态。这或许需要我们更精细化地选择化疗药物，更个体化地制定治疗方案，以及更前瞻性地监控治疗的远期后果。生命演化的剧本，充满了竞争、选择与偶然。而我们的每一次医疗干预，都在不经意间，为这剧本增添了新的篇章。通过这样的研究，我们正努力读懂这些篇章，希望能最终将笔握在自己手中，为生命书写一个更光明的结局。参考文献Uryu H, Saeki K, Haeno H, Kapadia CD, Furudate K, Nangalia J, Spencer Chapman M, Zhao L, Hsu JI, Zhao C, Chen S, Tanaka T, Li Z, Ogata S, Hanache S, Yang H, DiNardo C, Daver N, Pemmaraju N, Jain N, Ravandi F, Zhang J, Song X, Thompson E, Tang H, Little L, Gumbs C, Orlowski RZ, Qazilbash M, Bhalla K, Colla S, Kantarjian H, Kanagal-Shamanna R, Bueso-Ramos C, Nakada D, Al-Atrash G, Molldrem J, Futreal PA, Shpall E, Goodell M, Garcia-Manero G, Takahashi K. Clonal evolution of hematopoietic stem cells after autologous stem cell transplantation. Nat Genet. 2025 Jul 1. doi: 10.1038/s41588-025-02235-w. Epub ahead of print. PMID: 40596442.声明：本文仅用于分享，不代表平台立场，如涉及版权等问题，请尽快联系我们，我们第一时间更正，谢谢！往期热文：Cell | 打开生命发育“黑箱”！“虚拟胚胎”技术首次全景式再现早期器官形成过程Nature | “偷窥”大脑发育：首次4D直播“迷你大脑”发育，竟发现决定大脑区域的不是基因而是“细胞胶水”N Engl J Med | 移植免疫的“双刃剑”与“拆弹专家”：一项改写血液肿瘤治疗格局的新研究Cell | 生死一线间：揭秘血液的“命运开关”，竟是“启动”与“抑制”信号的致命博弈Science | 颠覆认知！细菌“内卷”的终极目的，竟是把邻居当“外卖”Cell | 学习中的“蝴蝶效应”：早期微小偏好如何通过多巴胺滚雪球，决定你的最终技能风格