Common Hematologic Malignancy Research Articles

Molecular Features and Treatment Paradigms of Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a common hematologic malignancy that is considered to be a disease of aging, and traditionally has been treated with induction chemotherapy, followed by consolidation chemotherapy and/or allogenic hematopoietic stem cell transplantation. More recently, with the use of next-generation sequencing and access to molecular information, targeted molecular approaches to the treatment of AML have been adopted. Molecular targeting is gaining prominence, as AML mostly afflicts the elderly population, who often cannot tolerate traditional chemotherapy. Understanding molecular changes at the gene level is also important for accurate disease classification, risk stratification, and prognosis, allowing for more personalized medicine. Some mutations are well studied and have an established gene-specific therapy, including FLT3 and IDH1/2, while others are being investigated in clinical trials. However, data on most known mutations in AML are still minimal and therapeutic studies are in pre-clinical stages, highlighting the importance of further research and elucidation of the pathophysiology involving these genes. In this review, we aim to highlight the key molecular alterations and chromosomal changes that characterize AML, with a focus on pathophysiology, presently available treatment approaches, and future therapeutic options.

Effective Prevention and Treatment of Acute Leukemias in Mice by Activation of Thermogenic Adipose Tissues.

Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are common hematological malignancies in adults. Despite considerable research advances, the development of standard therapies, supportive care, and prognosis for the majority of AML and ALL patients remains poor and the development of new effective therapy is urgently needed. Here, it is reported that activation of thermogenic adipose tissues (TATs) by cold exposure or β3-adrenergic receptor agonists markedly alleviated the development and progression of AML and ALL in mouse leukemia models. TAT activation (TATA) monotherapy substantially reduces leukemic cells in bone marrow and peripheral blood, and suppresses leukemic cell invasion, including hepatomegaly and splenomegaly. Notably, TATA therapy prolongs the survivals of AML- and ALL-bearing mice. Surgical removal of thermogenic brown adipose tissue (BAT) or genetic deletion of uncoupling protein 1 (UCP1) largely abolishes the TATA-mediated anti-leukemia effects. Metabolomic pathway analysis demonstrates that glycolytic metabolism, which is essential for anabolic leukemic cell growth, is severely impaired in TATA-treated leukemic cells. Moreover, a combination of TATA therapy with chemotherapy produces enhanced anti-leukemic effects and reduces chemotoxicity. These data provide a new TATA-based therapeutic paradigm for the effective treatment of AML, ALL, and likely other types of hematological malignancies.

Recent Updates in the Diagnosis and Management of Kidney Diseases in Multiple Myeloma

Multiple myeloma (MM) represents a difficult-to-treat plasma cell malignancy and the second most common hematologic malignancy in adults, significantly impacting kidney function. The spectrum of kidney involvement in MM is broad, encompassing electrolyte imbalances, tubular injury, and even rare glomerular diseases. The evolution of MM treatment modalities has led to notable improvements in the long-term survival of patients experiencing kidney-related complications. Over the past decade, groundbreaking therapeutic agents have emerged, including proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, selective inhibitors of nuclear export, and antibody-drug conjugates. These novel therapies have revolutionized the landscape of MM management, offering new hope for patients and challenging the traditional treatment paradigms. This comprehensive review explores recent advances in the diagnosis and management of MM, emphasizing the pivotal role of these innovative therapeutic agents in improving patient outcomes. We delve into the intricacies of diagnosing MM, highlighting the significance of early detection and precise diagnostic tools. We elucidate the evolving treatment strategies, emphasizing the mechanisms of action and clinical efficacy of the latest agents. This manuscript provides valuable insights into the ever-evolving field of MM management, shedding light on the remarkable progress achieved in enhancing the prognosis and quality of life of MM patients.

Targeting HMGCS1 restores chemotherapy sensitivity in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a common hematological malignancy with overall poor prognosis. Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory (RR) AML patients. Through clinical specimens, animal models and cell-level studies, we explored the specific mechanism of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1) in AML and the mechanism of targeting HMGCS1 to attenuate cell proliferation, increase chemotherapy sensitivity and improve the occurrence and development of AML. Here, we reveal that HMGCS1 is overexpressed in RR patients and negatively related to overall survival (OS). Knocking out HMGCS1 in AML cells attenuated cell proliferation and increased chemotherapy sensitivity, while stable overexpression of HMGCS1 had the opposite effects. Mechanistically, we identified that knockout of HMGCS1 suppressed mitogen-activated protein kinase (MAPK) pathway activity, while overexpression of HMGCS1 could remarkably enhance the pathway. U0126, a MEK1 inhibitor, offset the effects of HMGCS1 overexpression, indicating that HMGCS1 promotes RR AML through the MAPK pathway. Further, we verified that hymeglusin, a specific inhibitor of HMGCS1, decreases cell growth both in AML cell lines and primary bone marrow cells of AML patients. Furthermore, combination of hymeglusin and the common chemotherapeutic drug cytarabine and adriamycin (ADR) had synergistic toxic effects on AML cells. Our study demonstrates the important role of HMGCS1 in AML, and targeting this protein is promising for the treatment of RR AML.

P-423 Fertility outcomes of an egg donation program for hematologic cancer survivors: an 11-year retrospective cohort study

Abstract Study question What is the effectiveness of IVF/intracytoplasmic sperm injection with egg donation (IVF/ICSI-ED) in hematological cancer survivors (HCS) with reproductive desire and iatrogenic ovarian failure (IOF)? Summary answer The probability of clinical pregnancy and having a live birth does not significantly differ between women treated for hematological cancer and non-oncological patients using IVF/ICSI-ED. What is known already The most common hematological malignancies in women before or during reproductive age are lymphoma and leukemia. Oncological therapies cause premature ovarian failure, uterine fibrosis and infertility. Fertility preservation measures are not always possible or advisable. Egg vitrification in post-pubertal women has temporary implications as it requires ovarian stimulation; cryopreservation of ovarian tissue carries the risk of introducing back malignant cells. Fertility preservation is performed in 4-20% of cases: only 5% of patients have the chance to consult a reproductive specialist before cancer treatment. There are no published comparative studies on the effectiveness of ED in hematologic cancer survivors. Study design, size, duration We conducted a retrospective cohort study of 47 HCS with IOF, all of them nulliparous and without infertility diagnosis nor fertility preservation prior to oncological treatment and compared them with a control group (CG) of 19 infertile non-oncologic patients who underwent IVF/ICSI-ED with eggs from the same donors obtained during the same period of time (2012-2022). After evaluation by the center’s Oncofertility Committee, 45 HCS were eligible for IVF/ICSI-ED, and 23 agreed to undergo treatment. Participants/materials, setting, methods On the 47 patients HCS group we studied all the oncologic information: mean age at cancer diagnosis, mean age at IVF/ICS-ED treatment, type of tumor and oncologic treatment received. We compared the 23 patients HCS group with the 19 patients CG for: mean age of the egg recipient, mean age of the egg donor, single embryo transfers performed per patient, pregnancy and life bith rate per IVF/ICSI-ED treatment. We used chi-square statistic for the comparison. Main results and the role of chance The 47 women HCS group was aged between 25 to 50 years. The mean age at cancer diagnosis was 25.9 ± 7.6 years. The most frequent neoplasms were Hodgkin lymphoma (46.8%), non-Hodgkin lymphoma (21.2%), acute myeloid leukemia (12.7%), chronic myeloid leukemia (10.6%), other leukemias (8.5%). Lymphomas (68%) predominated over leukemias (32%). In this group 95.8% of the HCS were treated with chemotherapy: 21.2% as monotherapy, 14.8% combined with radiotherapy, 6.3% with surgery, and 6.3% with tyrosine kinase inhibitors (TKIs). Bone marrow transplantation was required in 46.8% of cases. At least 5 years elapsed from diagnosis to evaluation by the Oncology Committee. The mean egg recipient age was 36.5 ± 4.9 years for the HCS group and 41.3 ± 2.6 years for the CG (p < 0.05); there were no significant differences in the egg donor’s mean age (26.5±4.5 Vs 26.1±4.9, p=ns). We found no significant differences between the HCS and the CG in the mean single embryo transfers performed per patient (1.7 Vs 1.9, p=ns), in the pregnancy rate per ED cycle (88.4% vs 89.4%, p=ns), nor in the live birth rate per ED cycle (73% vs 64%, p=ns). Limitations, reasons for caution The retrospective nature of the study, the small number of cases and the under-recording of data in the medical history are the main limitations of this study. Wider implications of the findings It is important to have a comprehensive understanding of cancer therapies on fertility so that both doctors and patients can make informed decisions. Fertility preservation methods must be proposed before initiating oncological treatment, so multidisciplinary teamwork and timely referral to reproductive medicine centers specialized in fertility preservation are recommended. Trial registration number Not applicable

Physical activity and exercise motivation of multiple myeloma patients: a prospective cross-sectional study.

Multiple myeloma (MM) is the second most common hematological malignancy with its prevalence increasing. Patients with symptomatic MM can show numerous comorbidities, affecting their quality of life (QoL). Physical activity (PA) may improve QoL but is not a standardized intervention of comprehensive cancer centers (CCCs). Since data on the PA of patients with MM are scarce, we aimed to prospectively assess fitness levels and patients' motivation to join PA-interventions at our CCC. We generated an exercise questionnaire to interview consecutive patients MM. We prospectively collected data on (a) past and current PA, defined by the World Health Organization (WHO) recommendations, (b) knowledge on exercise effects, (c) exercise motivation, and (d) willingness to participate in PA-interventions. Demographics, comorbidities, response, progression-free survival (PFS), and overall survival (OS) were assessed in 211 symptomatic patients MM. While our patients were elderly and most showed bone involvement, their PA was similar to healthy individuals. Aerobic PA (≥ 60 minutes/week) was performed by 65%, and 25% exercised ≥ 150 minutes/week. WHO PA recommendations were fulfilled by 17% of patients. No sport activities or complete physical inactivity were observed in 35% and 16%, respectively. Notably, 38% were motivated to join MM-specific sport interventions. Self-reported knowledge of PA-induced benefits for patients cancer was high (82%), but only 27% knew which exercises were safe to perform. This study provides an overview of the PA of patients MM. Our results suggest that the PA of patients MM might not be much lower than in the age-matched general population.

PiRNAs and PIWI -like proteins in Multiple Myeloma and their future as biomarkers and therapy targets

Multiple Myeloma (MM) is the second most common hematological malignancy and one of the 19 most frequent types of cancer. Its diagnosis is a challenge due to the low rate of disease recognition, and diagnosis delays lead to the characteristic end-organ damage of the disease. New approaches to tackle that diagnosis challenge are required. Emerging evidence shows that Piwi-interacting RNAs (piRNA) promote increased methylation in MM cells. In this analysis, we delve into the latest discoveries surrounding piRNA biogenesis and functions, offering fresh perspectives on the possible uses of piRNAs in detection and diagnosis in MM. piRNA-823 increases in MM cells and positively correlates with the disease stage. Its tumorigenic actions in MM relate to intercellular communication between MM and vein endothelial cells. These findings provide the necessary information to highlight the possible role of piRNA-823 as a biomarker for MM diagnosis.

Recent Advances in The Definition of the Molecular Alterations Occurring in Multiple Myeloma.

Multiple myeloma (MM) is a disorder of the monoclonal plasma cells and is the second most common hematologic malignancy. MM initiation and progression are dependent upon complex genomic abnormalities. The current pathogenic model of MM includes two types of primary events, represented by chromosome translocations or chromosome number alterations resulting in hyperdiploidy. These primary molecular events are observed both in MM and in monoclonal gammopathy, its premalignant precursor. Subsequent genetic events allow the progression of monoclonal gammopathy to MM and, together with primary events, contribute to the genetic complexity and heterogeneity of MM. Newer therapies have considerably improved patient outcomes; however, MM remains an incurable disease and most patients experience multiple relapses. The dramatic progresses achieved in the analysis of the heterogeneous molecular features of different MM patients allowed a comprehensive molecular classification of MM and the definition of an individualized prognostic model to predict an individual MM patient's response to different therapeutic options. Despite these progresses, prognostic models fail to identify a significant proportion of patients destined to early relapse. Treatment strategies are increasingly. Based on disease biology, trials are enriched for high-risk MMs, whose careful definition and categorization requires DNA sequencing studies.

The Interplay between the DNA Damage Response (DDR) Network and the Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Multiple Myeloma.

The DNA damage response (DDR) network and the mitogen-activated protein kinase (MAPK) signaling pathway are crucial mechanisms for the survival of all living beings. An accumulating body of evidence suggests that there is crosstalk between these two systems, thus favoring the appropriate functioning of multi-cellular organisms. On the other hand, aberrations within these mechanisms are thought to play a vital role in the onset and progression of several diseases, including cancer, as well as in the emergence of drug resistance. Here, we provide an overview of the current knowledge regarding alterations in the DDR machinery and the MAPK signaling pathway as well as abnormalities in the DDR/MAPK functional crosstalk in multiple myeloma, the second most common hematologic malignancy. We also present the latest advances in the development of anti-myeloma drugs targeting crucial DDR- and MAPK-associated molecular components. These data could potentially be exploited to discover new therapeutic targets and effective biomarkers as well as for the design of novel clinical trials. Interestingly, they might provide a new approach to increase the efficacy of anti-myeloma therapy by combining drugs targeting the DDR network and the MAPK signaling pathway.

The multifaceted roles of extracellular vesicles for therapeutic intervention with non-Hodgkin lymphoma

Extracellular vesicles (EVs) contribute to the development of cancer in various ways. Non-Hodgkin lymphoma (NHL) is a cancer of mature lymphocytes and the most common hematological malignancy globally. The most common form of NHL, diffuse large B-cell lymphoma (DLBCL), is primarily treated with chemotherapy, autologous stem cell transplantation (ASCT), and/or chimeric antigen receptor T-cell (CAR-T) therapy. With NHL disease progression and its treatment, extracellular vesicles play remarkable roles in influencing outcomes. This finding can be utilized for therapeutic intervention to improve patient outcomes for NHL. This review focuses on the multifaceted roles of EVs with NHL and its potential for guiding patient care.

Abstract PO-020: ZBTB24 is a novel tumor suppressor and cooperates with CDKN2A to suppress B-cell lymphomagenesis

Abstract B-cell lymphoma is the most common hematological malignancy that accounts for the sixth highest mortality among all cancers. Despite recent improvements on combined chemotherapy and immunotherapy, treatments remain challenging due to complex genetic heterogeneity and molecular pathogenesis. To explore novel mechanisms in B-cell lymphomagenesis, we performed a genome-wide CRISPR knockout screen in the murine interleukin-3 (IL-3)-dependent Ba/F3 pro-B cell line and identified Zbtb24 as a putative target whose silencing leads to elevated proliferative signaling and reduced apoptosis, conferring IL-3-independent growth in Ba/F3 cells. Silencing of ZBTB24 also accelerated growth in multiple human B-cell lymphoma cell lines. ZBTB24 is a member of the zinc-finger and BTB domain containing transcription factor that is highly expressed in spleen and bone marrow. While it has been shown that ZBTB24 may play an important role in B-cell development and activation, its involvement in B-cell lymphoma has not been described. Analysis of publicly available datasets found that ZBTB24 copy number deletion occurs in various B-cell lymphomas, which frequently co-occurs with deletion of the tumor suppressor CDKN2A. Hence, we generated B-cell specific Zbtb24 single knockout and Zbtb24/Cdkn2a double knockout mice to explore the role of Zbtb24 in vivo. While Zbtb24 and Cdkn2a single knockout mice remained tumor-free or showed low penetrance of tumorigenesis, the double knockout mice developed lymphadenopathy and splenomegaly accompanied with accelerated mortality. Flow cytometry analysis of bone marrow, spleen, and lymph nodes revealed malignant B-cells. Subsequent transplantation of the splenic cells induced identical malignant B-cell lymphomagenesis and immunophenotype in athymic nude mice, further confirming its malignant identity. These results indicate that ZBTB24 is a novel tumor suppressor in B-cell malignancy. Ongoing studies are being conducted to understand the mechanistic basis for ZBTB24 tumor suppressive function that may involve transcriptional regulation of its target gene expression. This project is supported by the NIH R01CA232246, R01CA129536, and the John Colaizzi Endowment Fund. Citation Format: Rongrong Li, Namratha Sheshadri, Jianliang Shen, Junrong Yan, Jaeyong Jung, Muhammad Usama Tariq, Y Lynn Wang, Ping Xie, Wei-Xing Zong. ZBTB24 is a novel tumor suppressor and cooperates with CDKN2A to suppress B-cell lymphomagenesis [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-020.

Anesthesiologist’s Perspective on a Child with Acute Lymphoblastic Leukemia undergoing Neurosurgery: Case Report

Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in the pediatric age group. Anesthesia in such patients necessitates special considerations, in terms of disease progression and its respective treatment as well. We present a case of a 2-year-old child, a known case of ALL posted for drainage of multifocal brain abscess under general anesthesia. Anesthetic management of children with ALL presenting for neurosurgical procedures should focus on disease and its various systemic manifestations, treatment-related side effects, and anesthetic interactions which sometimes may be disastrous

The Epidemiological Particularities of Malignant Hemopathies in French Guiana: 2005-2014.

French Guiana is a French Overseas territory with singular features: it has a high prevalence of HIV and HTLV-1, its population is ethnically mixed, with widespread poverty, and up to 20% of the population lives in geographic isolation. In this context, we used registry data to estimate incidence and mortality due to hematological malignancies and to compare them with France and tropical Latin America. ICD codes C90 and C88 were compiled between 2005 and 2014. The direct standardization of age structure was performed using the world population. Survival analysis was performed, and Kaplan-Meier curves were drawn. The overall standardized incidence rate was 32.9 per 100,000 male years and 24.5 per 100,000 female years. Between 2005 and 2009, the standardized incidence rate was 29.6 per 100,000 among men and 23.6 per 100,000 among women, and between 2010 and 2014, it was 35.6 per 100,000 among men and 25.2 per 100,000 among women. Multiple myeloma/plasmocytoma and mature t/NK cell lymphomas, notably adult t-cell lymphoma/leukemia due to HTLV-1 infection, were the two most common hematologic malignancies and causes of death. Non-Hodgkin's lymphoma incidence estimates were greater than global estimates. After adjusting for age, sex, and type of malignancy, people born in a foreign country independently had a poorer case-fatality rate, presumably reflecting difficulties in accessing care. The epidemiology of hematological malignancies in French Guiana has features that distinguish it from mainland France or from Latin America. The incidence of multiple myeloma and adult t-cell lymphoma/leukemia was significantly greater in French Guiana than in France or other Latin American countries.

Identification and evaluation of a six-lncRNA prognostic signature for multiple myeloma

PurposeMultiple myeloma (MM) is the second most common hematologic malignancy, and there is no cure for this disease. This study aimed to explore the prognostic value of long noncoding RNAs (lncRNAs) in MM and to reveal related immune and chemotherapy resistance mechanisms.MethodsIn this study, lncRNA profiles from the Multiple Myeloma Research Foundation (MMRF) and Gene Expression Omnibus (GEO) databases were analyzed to identify lncRNAs linked to MM patient survival. A risk assessment model stratified patients into high- and low-risk groups, and survival was evaluated. Additionally, a triple-ceRNA (lncRNA–miRNA–mRNA) network was constructed, and functional analysis was performed. The research also involved immune function analysis and chemotherapy drug sensitivity assessment using oncoPredict and the GDSC dataset.ResultsWe identified 422 lncRNAs significantly associated with overall survival in MM patients and ultimately focused on the 6 with the highest prognostic value. These lncRNAs were used to develop a risk score formula that stratified patients into high- and low-risk groups. Kaplan–Meier analysis revealed shorter survival in high-risk patients. We integrated this lncRNA signature with clinical parameters to construct a nomogram for predicting MM prognosis. Additionally, a triple-ceRNA network was constructed to reveal potential miRNA targets, coding genes related to these lncRNAs and significantly enriched pathways. Immune checkpoint gene expression and immune cell composition were also analyzed in relation to the lncRNA risk score. Finally, using the oncoPredict tool, we observed that high-risk patients exhibited decreased sensitivity to key MM chemotherapeutics, suggesting that lncRNA profiles are linked to chemotherapy resistance.

Survival shifts in multiple myeloma: Evaluating the impact of therapeutic advances and racial disparities after a decade of change.

e19509 Background: Multiple myeloma (MM) is the second most common hematologic malignancy and is considered an incurable disease. However, the last two decades have witnessed the emergence of new therapies that have improved overall survival by several folds. In the current study, we are examining the evolving trends in age-adjusted incidence and relative survival among myeloma patients over the last 20 years, specifically focusing on discerning disparities in these trends based on racial classifications. Methods: We performed a retrospective cohort study using the SEER Plus Data, 12 registries, Nov 2022 Sub (1992-2020) to calculate the age-adjusted incidence and relative survival rate (RSR) of MM in the US in two specific time intervals 2001-2010 & 2011-2020 consistent with changes in MM treatment during 2011-2020 including the emergence of immunomodulatory drugs (IMiDs). The year of diagnosis, sex, and race data were available for each case. We excluded cases diagnosed before 2001 and after 2020. Patients were stratified by sex and categorized into two racial groups: White and Black. The 60-month (5-year) and 116-month (used as a 10-year estimate) RSR and age-adjusted incidence rate were calculated for the cohort and each racial group. We calculated survival utilizing the Kaplan-Meier method. Using the log-rank test, we also found hazard ratios (HR), with the corresponding CI for each racial group stratified by sex. Results: We investigated MM incidence and survival rate trends over two decades while considering gender and race. The age-adjusted incidence rate showed a significant overall increase from 6.5 to 7.4 per 100,000, with changes in gender-specific rates. Higher incidence rates among Black populations were noted. Cohort relative survival analysis revealed improved median survival (53 to 83 months) and increased relative survival rate both at five years (46.4% to 56.3%) and at ten years (28.8% to 40.8%). An investigation based on race revealed substantial improvements among both White and Black populations. The HR (Table) emphasized the improved survival outcomes for patients diagnosed in period two across genders and races. Conclusions: The study highlights the changes in the incidence and survival rates of MM. Notably, MM incidence has seen a significant rise in the last decade, particularly among the Black population. The survival of patients diagnosed between 2011 and 2020 revealed statistically significant improvement at both the 5- and 10-year mark compared to patients diagnosed between 2001 and 2010. [Table: see text]

Long non-coding RNA PXN-AS1 promotes glutamine synthetase-mediated chronic myeloid leukemia BCR::ABL1-independent resistance to Imatinib via cell cycle signaling pathway

BackgroundChronic myeloid leukemia (CML) is a common hematological malignancy, and tyrosine kinase inhibitors (TKIs) represent the primary therapeutic approach for CML. Activation of metabolism signaling pathway has been connected with BCR::ABL1-independent TKIs resistance in CML cells. However, the specific mechanism by which metabolism signaling mediates this drug resistance remains unclear. Here, we identified one relationship between glutamine synthetase (GS) and BCR::ABL1-independent Imatinib resistance in CML cells.MethodsGS and PXN-AS1 in bone marrow samples of CML patients with Imatinib resistance (IR) were screened and detected by whole transcriptome sequencing. GS expression was upregulated using LVs and blocked using shRNAs respectively, then GS expression, Gln content, and cell cycle progression were respectively tested. The CML IR mice model were established by tail vein injection, prognosis of CML IR mice model were evaluated by Kaplan–Meier analysis, the ratio of spleen/body weight, HE staining, and IHC. PXN-AS1 level was blocked using shRNAs, and the effects of PXN-AS1 on CML IR cells in vitro and in vivo were tested the same as GS. Several RNA-RNA tools were used to predict the potential target microRNAs binding to both GS and PXN-AS1. RNA mimics and RNA inhibitors were used to explore the mechanism through which PXN-AS1 regulates miR-635 or miR-635 regulates GS.ResultsGS was highly expressed in the bone marrow samples of CML patients with Imatinib resistance. In addition, the lncRNA PXN-AS1 was found to mediate GS expression and disorder cell cycle in CML IR cells via mTOR signaling pathway. PXN-AS1 regulated GS expression by binding to miR-635. Additionally, knockdown of PXN-AS1 attenuated BCR::ABL1-independent Imatinib resistance in CML cells via PXN-AS1/miR-635/GS/Gln/mTOR signaling pathway.ConclusionsThus, PXN-AS1 promotes GS-mediated BCR::ABL1-independent Imatinib resistance in CML cells via cell cycle signaling pathway.Graphic

G-Quadruplex Forming DNA Sequence Context Is Enriched around Points of Somatic Mutations in a Subset of Multiple Myeloma Patients.

Multiple myeloma (MM) is the second most common hematological malignancy, which remains incurable despite recent advances in treatment strategies. Like other forms of cancer, MM is characterized by genomic instability, caused by defects in DNA repair. Along with mutations in DNA repair genes and genotoxic drugs used to treat MM, non-canonical secondary DNA structures (four-stranded G-quadruplex structures) can affect accumulation of somatic mutations and chromosomal abnormalities in the tumor cells of MM patients. Here, we tested the hypothesis that G-quadruplex structures may influence the distribution of somatic mutations in the tumor cells of MM patients. We sequenced exomes of normal and tumor cells of 11 MM patients and analyzed the data for the presence of G4 context around points of somatic mutations. To identify molecular mechanisms that could affect mutational profile of tumors, we also analyzed mutational signatures in tumor cells as well as germline mutations for the presence of specific SNPs in DNA repair genes or in genes regulating G-quadruplex unwinding. In several patients, we found that sites of somatic mutations are frequently located in regions with G4 context. This pattern correlated with specific germline variants found in these patients. We discuss the possible implications of these variants for mutation accumulation and specificity in MM and propose that the extent of G4 context enrichment around somatic mutation sites may be a novel metric characterizing mutational processes in tumors.

Mesenchymal stem cells-macrophages crosstalk and myeloid malignancy.

As major components of the tumor microenvironment, both mesenchymal stem cells (MSCs) and macrophages can be remodelled and exhibit different phenotypes and functions during tumor initiation and progression. In recent years, increasing evidence has shown that tumor-associated macrophages (TAMs) play a crucial role in the growth, metastasis, and chemotherapy resistance of hematological malignancies, and are associated with poor prognosis. Consequently, TAMs have emerged as promising therapeutic targets. Notably, MSCs exert a profound influence on modulating immune cell functions such as macrophages and granulocytes, thereby playing a crucial role in shaping the immunosuppressive microenvironment surrounding tumors. However, in hematological malignancies, the cellular and molecular mechanisms underlying the interaction between MSCs and macrophages have not been clearly elucidated. In this review, we provide an overview of the role of TAMs in various common hematological malignancies, and discuss the latest advances in understanding the interaction between MSCs and macrophages in disease progression. Additionally, potential therapeutic approaches targeting this relationship are outlined.

Abstract P15: Aberrant Non-canonical NF-κB Signalling Reprograms the Epigenome Landscape to Drive Oncogenic Transcriptomes in Multiple Myeloma

Abstract Activation of the NF-κB pathway is recognized to be necessary for the survival and progression of haematological cancers including Multiple Myeloma (MM). In particular, recurrent genetic lesions resulting in the chronic induction of non-canonical NF-κB (ncNF-κB) signalling have been exclusively linked to MM. Such mutations among patients are associated with significant proliferative and metastatic advantages and have been causally linked to treatment resistance. How the constitutive activity of ncNF-κB transcription factors can support such adaptations in this common haematological malignancy has been a fundamental question in cancer. In this study, we captured the epigenomic landscape of patient-derived MM cell lines harbouring recurrent NF-κB activating mutations through perturbation of nfkb2/p52 and integrated these cis-regulatory changes with MM patient epigenome data. Here, we find that sustained NF-κB/p52 levels resulting from such mutations favours the recruitment of enhancers beyond the normal B-cell repertoire. Furthermore, through targeted disruption of p52, we characterise how such enhancers are complicit in the formation of super-enhancers and the establishment of cis-regulatory interactions with myeloma dependencies during constitutive activation of p52. Finally, we functionally validate the pathological impact of these cis-regulatory modules on cell and tumour phenotypes using in vitro and in vivo models, confirming RGS1 as a novel p52-dependent myeloma driver. We conclude that the divergent epigenomic reprogramming enforced by aberrant non-canonical NF-κB signalling potentiates transcriptional programs beneficial for multiple myeloma progression. Citation Format: Daniel A. Ang, Jean-Michel Carter, Kamalakshi Deka, Joel H.L. Tan, Jianbiao Zhou, Qingfeng Chen, Wee Joo Chng, Nathan Harmston, Yinghui Li. Aberrant Non-canonical NF-κB Signalling Reprograms the Epigenome Landscape to Drive Oncogenic Transcriptomes in Multiple Myeloma [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P15.

Pathogenetic parallels and clinical relationships of HIV infection and Hodgkin’s lymphoma

Aim: to show the importance of the features of the development of Hodgkin’s lymphoma (HL) against the background of HIV infection, possible clinical relationships and consequences of simultaneous diseases in patients, as well as complex therapy. Material and methods. The article presents an analytical review of the problem and retrospective data on 63 patients with HIV[1]associated HL (HIV-HL) who were diagnosed with HL in St. Petersburg hospitals in the period 2000–2017. For the diagnosis of HIV-HL, regulated morphological, immunohistochemical, instrumental and laboratory research methods were used, the tumor stage was determined based on the Cotswolds-modified Ann Arbor classification. The diagnosis of HIV infection was confirmed by the detection of specific antibodies to HIV (and the p24 antigen) during serological and enzyme immunoassay of blood, by immune blotting. The number of copies of HIV RNA and the number of CD4 lymphocytes in the blood of patients were determined using commercial test systems approved for use in the territory of the Russian Federation. The analysis of overall survival was performed using the Kaplan–Meyer method. Statistical processing of the research results was performed using statistical programs MS Excel 2010, GraphPad Prism 8 (GraphPad Software, Inc., USA), SPSS version 22.Results. The study group was dominated by men (73%), the median age was 32 years, in 16 (25.4%) patients HIV and HL were detected simultaneously. The number of CD4 lymphocytes > 500 cl/μl at the HL debut was noted in 33.3% of patients, patients with severe immunosuppression prevailed (50–250 cl/μl in 20 (31.7%), 250–500 cl/μl in 11 (17.5%), less than 50 cl/μl in 11 (17.5%). The amount of HIV RNA>400 kop/ml was noted in 82.5%, HIV infection at stages 4B-5 was detected in 89% of cases, at the time of detection of HL ART was performed in 16 patients. EBV coinfection (77.8%), cytomegalovirus (60%), viral hepatitis (55.6%) with a predominance of viral hepatitis C, common opportunistic infections (tuberculosis, pneumocystis pneumonia, toxoplasmosis of the brain, common candidiasis), simultaneously occurring from 1 to 3 infections were observed in 77.8%. Stage IV HL was established in 54%, III — in 22%, II — in 24% of patients, the presence of B-symptoms was confirmed in 73% of cases. The predominant histological variant of HIV-HL was nodular sclerosis (58 patients), mixed[1]cell sclerosis in 4 patients, with lymphoid predominance in 1 case. Extranodal lesions were observed in 34 (54%), complications of the tumor process in 33 (37.5%) patients. 42 (66.7%) patients received antitumor treatment for HL: line 1 according to the ABVD scheme — 85.7% (80% achieved PET-negative complete remission (CR), according to the VEASORR esc or VEASORR schemes — 33.3%; line 2 — according to the ICE or DHAP schemes (n=10). An objective response was noted in 4 patients, PET-negative response in 2 of them, partial PET-positive regression in 2 patients. Progression was observed in 2 people. Autologous bone marrow transplantation was performed in 2 patients (in partial PET-positive regression); line 3 (n=3) — chemoimmunotherapy with bendamustine, gemcitabine (2 patients underwent autologous bone marrow transplantation). The cumulative life expectancy of patients for 1 year and 2 years was 44% and 37%, respectively, 1-year overall survival was 75%, 2-year — 60%. The factors negatively affecting survival and life expectancy were tumor progression and complications, ECOG≥2 (p=0.0001), candidiasis, pneumonia (p=0.001), viral hepatitis B and C (p=0.045), lack of antitumor treatment and ART (p=0.0001), age younger than 40 years, central nervous system damage, the presence of 1 or more concomitant infections (p=0.024). Conclusion. HIV-HL is one of the most common hematological malignancies, characterized by heterogeneity in its manifestations, polymorphism of pathogenetic and clinical features and relationships. During the dispensary supervision of PLHIV, special attention should be paid to the factors of an unfavorable prognosis of the disease, the timeliness of the appointment of ART and the assessment of the risks of developing lymphoproliferative diseases within the framework of the immune system restoration syndrome (IRIS) in order to increase their survival and quality of life. Further research is needed on the pathogenesis, early diagnosis and effective treatment of lymphomas associated with the human immunodeficiency virus