Chemobrain in blood cancers: How chemotherapeutics interfere with the brain's structure and functionality, immune system, and metabolic functions.

Cancer treatment brings about a phenomenon not fully clarified yet, termed chemobrain. Its strong negative impact on patients' well-being makes it a trending topic in current research, interconnecting many disciplines from clinical oncology to neuroscience. Clinical and animal studies have often reported elevated concentrations of proinflammatory cytokines in various types of blood cancers. This inflammatory burst could be the background for chemotherapy-induced cognitive deficit in patients with blood cancers. Cancer environment is a dynamic interacting system. The review puts into close relationship the inflammatory dysbalance and oxidative/nitrosative stress with disruption of the blood-brain barrier (BBB). The BBB breakdown leads to neuroinflammation, followed by neurotoxicity and neurodegeneration. High levels of intracellular reactive oxygen species (ROS) induce the progression of cancer resulting in increased mutagenesis, conversion of protooncogenes to oncogenes, and inactivation of tumor suppression genes to trigger cancer cell growth. These cell alterations may change brain functionality, as well as morphology. Multidrug chemotherapy is not without consequences to healthy tissue and could even be toxic. Specific treatment impacts brain function and morphology, functions of the immune system, and metabolism in a unique mixture. In general, a chemo-drug's effects on cognition in cancer are not direct and/or in-direct, usually a combination of effects is more probable. Last but not least, chemotherapy strongly impacts the immune system and could contribute to BBB disruption. This review points out inflammation as a possible mechanism of brain damage during blood cancers and discusses chemotherapy-induced cognitive impairment.

IL-27-engineered CAR.19-NK-92 cells exhibit enhanced therapeutic efficacy.

Chimeric antigen receptor (CAR) engineering of natural killer (NK) cells has shown promising results in early-phase clinical studies. However, advancing CAR-NK cell therapeutic efficacy is imperative. In this study, we investigated the impact of a fourth-generation CD19-targeted CAR (CAR.19) coexpressing IL-27 on NK-92 cells. We observed a significant improvement in NK-92 cell proliferation and cytotoxicity activity against B-cell cancer cell lines, both in vitro and in a xenograft mouse B-cell lymphoma model. Our systematic transcriptome analysis of the activated NK-92 CAR variants further supports the potential of IL-27 in fourth-generation CARs to overcome limitations of NK cell-based targeted tumor therapies by providing essential growth and activation signals. Integrating IL-27 into CAR-NK cells emerges as a promising strategy to enhance their therapeutic potential and elicit robust responses against cancer cells. These findings contribute substantially to the mounting evidence supporting the potential of fourth-generation CAR engineering in advancing NK cell-based immunotherapies.

A Comprehensive Review of Cancer Drug-Induced Cardiotoxicity in Blood Cancer Patients: Current Perspectives and Therapeutic Strategies.

OPINION STATEMENT: Cardiotoxicity has emerged as a serious outcome catalyzed by various therapeutic targets in the field of cancer treatment, which includes chemotherapy, radiation, and targeted therapies. The growing significance of cancer drug-induced cardiotoxicity (CDIC) and radiation-induced cardiotoxicity (CRIC) necessitates immediate attention. This article intricately unveils how cancer treatments cause cardiotoxicity, which is exacerbated by patient-specific risks. In particular, drugs like anthracyclines, alkylating agents, and tyrosine kinase inhibitors pose a risk, along with factors such as hypertension and diabetes. Mechanistic insights into oxidative stress and topoisomerase-II-B inhibition are crucial, while cardiac biomarkers show early damage. Timely intervention and prompt treatment, especially with specific agents like dexrazoxane and beta-blockers, are pivotal in the proactive management of CDIC.

Expression variations of DNA damage response genes ATM and ATR in blood cancer patients.

Hematological malignancies (HM) constitute a variety of cancers originating in blood, bone marrow (BM), and lymphatic systems. During the last two decades, the incidence of HM has dramatically increased worldwide. The etiology of HM is still debatable. Genetic instability is a major risk factor for HM. DDR network is a complex signal transduction cellular machinery that detects DNA damage and activates cellular repair factors, thus maintaining genomic integrity. DDR network detects a variety of DNA damage and triggers the activation of cell cycle control, DNA repair, senescence, and apoptosis. Among the DNA repairing pathways, the DNA damage response (DDR) pathway includes DNA damage signaling apparatus such as ATM and ATR genes. ATM tends to detect double-strand breaks (DSBs) while ATR detects single-strand DNA (ssDNA). The study was conducted to observe the expression deregulations of DNA damage response (DDR) pathway genes (ATM, ATR) at mRNA level in 200 blood cancer patients and 200 controls. The real-time PCR was used to analyze the expression of the target genes. The expression results showed statistically significant downregulation of ATM (p < 0.0001) and ATR (p < 0.0001) genes in blood cancer patients vs. controls. Moreover, a significant downregulation of ATM (p < 0.0001) and ATR (p < 0.0001) was obtained in chemotherapy-treated patients vs. healthy controls. The results suggest that dysregulation in ATM and ATR genes may be associated with increased blood cancer risk.

Efficacy, safety, and cost-minimization analysis of axicabtagene ciloleucel and tisagenlecleucel CAR T-Cell therapies for treatment of relapsed or refractory follicular lymphoma.

Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are chimeric antigen receptor (CAR) T-cell therapies used to treat adult patients with relapsed or refractory follicular lymphoma (rrFL) after two or more lines of systemic therapy. In the absence of head-to-head clinical trials, this study aimed to compare the efficacy, safety, and cost of axi-cel and tisa-cel in the treatment of rrFL after at least two lines of treatment. Overall response rate (ORR) and safety signals were compared using reporting odds ratios (RORs) with 95% confidence intervals (CIs) at p < 0.05. Progression-free survival (PFS), duration of response (DoR), and overall survival (OS) were compared using the Kaplan?Meier method with a log-rank test. Cost and cost-minimization analyses of drug acquisition, drug administration, serious adverse events (AEs), and relapsed management were calculated. Costs were extracted from the IBM-Micromedex Red Book, Centers for Medicare and Medicaid Services, and existing literature. Statistical analyses were conducted using Microsoft Excel and R version 4.0.5. No statistically significant differences were observed between axi-cel and tisa-cel in terms of ORR, DoR, and OS (p > 0.05). PFS was significantly better with tisa-cel (p < 0.05). Axi-cel was significantly associated with higher incidences of CRS, neurologic events, and grade 3-4 AEs than tisa-cel (ROR > 1, p < 0.05). Axi-cel and tisa-cel cost $512,021 and $450,885 per patient, respectively, resulting in savings of US$61,136 with tisa-cel over axi-cel. Tisa-cel appears to have a better safety profile, fewer serious AEs, lower mortality rate, and lower cost than axi-cel.

Assessing awareness of blood cancer symptoms and barriers to symptomatic presentation: measure development and results from a population survey in the UK.

BACKGROUND: Low levels of cancer awareness may contribute to delays in seeking medical help and subsequent delays in diagnosis. For blood cancer this may be a particularly prominent problem due to the high prevalence of undifferentiated symptoms such as bodily pain, weakness, nausea and weight loss, resulting in low symptom awareness. The delay is exacerbated by the dismissal of similar symptoms which are often interpreted as mild disease, resulting in multiple consultations prior to diagnosis. This study describes the development of a Cancer Awareness Measure for Blood Cancer (Blood CAM) and presents results from a population-representative survey using the measure. METHODS: A rapid systematic review identified constructs relevant to blood cancer. Items were taken from previous awareness measures and other literature and reviewed by expert groups including health care professionals and patients. Cognitive interviews were conducted with ten members of the public to check comprehension and clarity. A total sample of 434 participants completed the survey at Time 1 and n = 302 at Time 2 (two weeks later). RESULTS: Internal reliability was high across the different constructs included in the questionnaire (> 0.70) and test-retest reliability was moderate to good (0.49-0.79). The most commonly recognised blood cancer symptoms were unexplained weight loss (68.9%) and unexplained bleeding (64.9%) and the least commonly recognised symptoms were night sweats (31.3%) breathlessness and rash/itchy skin (both 44%). In terms of symptom experience, fatigue was the most commonly reported symptom (26.7%) followed by night sweats (25.4%). Exploratory factor analysis of barriers to presenting at primary care revealed three distinct categories of barriers; emotional, external/practical and service/healthcare professional related. Service and emotional barriers were most common. CONCLUSIONS: We developed a valid and reliable tool to assess blood cancer awareness and showed variable awareness of blood cancer symptoms which can help target public health campaigns. We also incorporated additional measures (e.g. confidence to re-consult, ability to understand symptoms) that could be used to tailor public messaging for blood cancer and for other harder to suspect and diagnose cancers.

The relationship between patient enablement and help-seeking in the context of blood cancer symptoms.

OBJECTIVE: Approaches to improve earlier diagnosis of cancer often focus on symptom awareness as a key driver of help-seeking behaviour and other psychological influences are less well understood. This is the first study to explore the role of patient enablement on help-seeking for people experiencing potential blood cancer symptoms. METHODS: A cross-sectional, nationally representative survey was completed by 434 respondents (>18 years). Questions asked about symptom experiences, medical help-seeking and re-consultation. Existing patient enablement items were included in the newly developed Blood Cancer Awareness Measure. We collected data on patient socio-demographic characteristics. RESULTS: Of those responding to the survey 224/434 (51.6%) reported experiencing at least one potential blood cancer symptom. Half of those experiencing symptoms (112/224) had sought medical help. Results from logistic regression analysis showed that higher scores on patient enablement were associated with being less likely to seek help (Odds Ratio [OR] 0.89, Confidence Interval [CI] 0.81-0.98) after controlling for socio-demographics. Separate analyses showed that higher enablement was associated with being more comfortable to re-consult if symptoms didn't go away or got worse (OR 1.31, CI 1.16-1.48); after a test result suggested there was nothing to worry about, but symptoms persisted (OR 1.23, CI 1.12-1.34) or to request further tests, scans or investigations (OR 1.31, CI 1.19-1.44). CONCLUSIONS: Contrary to our hypotheses, patient enablement was associated with lower likelihood of help-seeking for potential blood cancer symptoms. Yet enablement appears to play an important role in likelihood of re-consulting when symptoms persist, get worse or need further investigation.

Fitness and metabolic response to exercise in young adult survivors of childhood lymphoma.

PURPOSE: Childhood lymphoma survivors (CLSs) are at high risk of reduced daily activity. This work studied metabolic substrate use and cardiorespiratory function in response to exercise in CLSs. METHODS: Twenty CLSs and 20 healthy adult controls matched for sex, age, and BMI took an incremental submaximal exercise test to determine fat/carbohydrate oxidation rates. Resting echocardiography and pulmonary functional tests were performed. Physical activity level, and blood metabolic and hormonal levels were measured. RESULTS: CLSs reported more physical activity than controls (6317 ± 3815 vs. 4268 ± 4354 MET-minutes/week, p = 0.013), had higher resting heart rate (83 ± 14 vs. 71 ± 13 bpm, p = 0.006), and showed altered global longitudinal strain (- 17.5 ± 2.1 vs. - 19.8 ± 1.6%, p = 0.003). We observed no difference in maximal fat oxidation between the groups, but it was reached at lower relative exercise intensities in CLSs (Fatmax 17.4 ± 6.0 vs. 20.1 ± 4.1 mL/kg, p = 0.021). At V̇O2 peak, CLSs developed lower relative exercise power (3.2 ± 0.9 vs. 4.0 ± 0.7 W/kg, p = 0.012). CONCLUSION: CLSs reported higher levels of physical activity but they attained maximal fat oxidation at lower relative oxygen uptake and applied lower relative power at V̇O2 peak. CLSs may thus have lower muscular efficiency, causing greater fatigability in response to exercise, possibly related to chemotherapy exposure during adolescence and childhood. Long-term follow-up is essential and regular physical activity needs to be sustained.

A systematic review of physical function tests as predictors of key clinical outcomes for adults with blood cancers.

PURPOSE: To determine which standardized physical performance tests are being used specifically in the assessment of adult patients before, during, or after undergoing treatment for hematologic malignancy and which of these functional tests have been demonstrated to have a correlation with key objective clinical outcome measures including mortality, progression-free survival, complete remission, hospital readmissions, emergency department visits, and hospital length of stay. METHODS: PubMed/MEDLINE electronic databases were searched up to June 2021. Searches were restricted to English language. All resulting studies from the electronic database search were assessed by two reviewers for original research with physical performance data exclusive to patients with hematological malignancy. Studies with confounding intervention or the inclusion of pediatric patients were excluded. The quality of the remaining studies was assessed using PRISMA guidelines and Tooth Criteria by two reviewers, using a third reviewer to resolve any discrepancies. The main characteristics of each article, including sample size, population characteristics, physical performance testing methods, and significant and non-significant findings were extracted and compared. Additionally, one reviewer performed a literature review of the safety of physical performance testing. RESULTS: One thousand two hundred fifty-six screened database results resulted in 14 studies included in the systematic review. All studies scored ≥ 0.59 on the Tooth Criteria, indicating moderate to high quality of reporting. Our review found six recurring measures of objective physical function assessed for correlation with clinical outcomes, primarily morbidity and mortality. The heterogeneity of each study precluded aggregate data analysis. CONCLUSIONS: This review was a first step in evaluating which objective physical performance tests are best suited for identifying functional impairment before, during, and after oncologic treatment for adults with blood cancers. Additional studies are needed to determine the optimal objective functional measures to use as a guide in clinical decision-making in the hematologic patient population.

Epigenetic Modification of Cytosines in Hematopoietic Differentiation and Malignant Transformation.

The mammalian DNA methylation landscape is established and maintained by the combined activities of the two key epigenetic modifiers, DNA methyltransferases (DNMT) and Ten-eleven-translocation (TET) enzymes. Once DNMTs produce 5-methylcytosine (5mC), TET proteins fine-tune the DNA methylation status by consecutively oxidizing 5mC to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives. The 5mC and oxidized methylcytosines are essential for the maintenance of cellular identity and function during differentiation. Cytosine modifications with DNMT and TET enzymes exert pleiotropic effects on various aspects of hematopoiesis, including self-renewal of hematopoietic stem/progenitor cells (HSPCs), lineage determination, differentiation, and function. Under pathological conditions, these enzymes are frequently dysregulated, leading to loss of function. In particular, the loss of DNMT3A and TET2 function is conspicuous in diverse hematological disorders, including myeloid and lymphoid malignancies, and causally related to clonal hematopoiesis and malignant transformation. Here, we update recent advances in understanding how the maintenance of DNA methylation homeostasis by DNMT and TET proteins influences normal hematopoiesis and malignant transformation, highlighting the potential impact of DNMT3A and TET2 dysregulation on clonal dominance and evolution of pre-leukemic stem cells to full-blown malignancies. Clarification of the normal and pathological functions of DNA-modifying epigenetic regulators will be crucial to future innovations in epigenetic therapies for treating hematological disorders.

Preparing Patients to Communicate with Their Doctors About Clinical Trials as a Treatment Option: Impact of a Novel Video Intervention for Patients with a Blood Cancer and Their Caregivers.

Cancer clinical trials (CCTs) are imperative for advancing cancer treatment and providing treatment options for patients; however, many barriers exist to offering and enrolling interested and eligible patients. It is crucial to equip patients and caregivers with communication skills that help them initiate and navigate conversations about the option of receiving treatment within a CCT. The aim was to assess the acceptability and impact of a novel video training for patients and caregivers that models strategies for patient-provider communication using the PACES method of healthcare communication and provides information about CCTs. The three-module training was implemented among blood cancer patients and caregivers. Using a single-arm pre-post study design, self-report surveys assessed changes in knowledge, confidence in using the PACES method, and perceived importance of, confidence in, and behavioral intention related to talking with doctors about CCTs. The Patient Report of Communication Behavior (PRCB) scale was administered. Among 192 participants, post-intervention knowledge gains were evident (p < 0.001). Confidence, importance, and likelihood to communicate about CCTs and confidence about using PACES also increased (p < 0.001); females who had never previously spoken to a provider about CCTs demonstrated greater impact (p = 0.045) than other genders. PRCB mean scores increased among patients 65+ who had never spoken to a provider about CCTs, with greater change than patients <65 (p = 0.001). This educational intervention for patients and caregivers increased knowledge about CCTs, skills in communicating with doctors about care and CCTs, and readiness to initiate conversations about CCTs as a potential treatment option.

Living with a blood cancer in later life: The complex challenges and related support needs of adults aged 75 and older.

OBJECTIVES: This study investigated the challenges and support needs of adults aged 75 and older during and after treatment for a blood cancer to aid targeted supportive resource development. METHODS: Adults aged 75 and older with a blood cancer participated in in-depth, semi-structured interviews about challenges and unmet support needs. Participants recruited through The Leukemia & Lymphoma Society were (1) in treatment or previously in treatment for a blood cancer at age 75 or older and (2) living in the United States or its territories. A thematic analysis was conducted with findings compared between 2 groups: (1) chronic -living with a chronic blood cancer; (2) acute -living with an acute blood cancer or both an acute and chronic blood cancer. RESULTS: Participants (n = 50) ranged from 75 to 91 years old. Both groups described similar experiences and identified 5 challenges and support needs: (1) socioemotional impact, (2) activities of daily living and instrumental activities of daily living (ADLs/iADLs), (3) uncertainty management, (4) treatment-related stressors, and (5) COVID-19-related strain. Properties for these themes illustrate challenges and support needs, with some differences between groups. For instance, those living with a chronic blood cancer highlighted financial strain with treatment-related stressors, while those with an acute blood cancer focused more on iADLs. SIGNIFICANCE OF RESULTS: Findings inform an agenda for targeted resource development for older adults with a blood cancer nearing the end of the life span. Results demonstrate the need for supportive services and family communication interventions to help patients manage iADLs and navigate socioemotional needs and challenges.

Nanoparticle-Based Approaches for Treatment of Hematological Malignancies: a Comprehensive Review.

Blood cancer, also known as hematological malignancy, is one of the devastating types of cancer that has significantly paved its mortality mark globally. It persists as an extremely deadly cancer type and needs utmost attention owing to its negligible overall survival rate. Major challenges in the treatment of blood cancer include difficulties in early diagnosis, as well as severe side effects resulting from chemotherapy. In addition, immunotherapies and targeted therapies can be prohibitively expensive. Over the past two decades, scientists have devised a few nanoparticle-based drug delivery systems aimed at overcoming this challenge. These therapeutic strategies are engineered to augment the cellular uptake, pharmacokinetics, and effectiveness of anticancer drugs. However, there are still numerous types of nanoparticles that could potentially improve the efficacy of blood cancer treatment, while also reducing treatment costs and mitigating drug-related side effects. To the best of our knowledge, there has been limited reviews published on the use of nano-based drug delivery systems for the treatment of hematological malignancies. Therefore, we have made a concerted effort to provide a comprehensive review that draws upon recent literature and patents, with a focus on the most promising results regarding the use of nanoparticle-based approaches for the treatment of hematological malignancies. All these crucial points covered under a common title would significantly help researchers and scientists working in the area.

JAK-STAT core cancer pathway: An integrative cancer interactome analysis.

Through a comprehensive review and in silico analysis of reported data on STAT-linked diseases, we analysed the communication pathways and interactome of the seven STATs in major cancer categories and proposed rational targeting approaches for therapeutic intervention to disrupt critical pathways and addictions to hyperactive JAK/STAT in neoplastic states. Although all STATs follow a similar molecular activation pathway, STAT1, STAT2, STAT4 and STAT6 exert specific biological profiles associated with a more restricted pattern of activation by cytokines. STAT3 and STAT5A as well as STAT5B have pleiotropic roles in the body and can act as critical oncogenes that promote many processes involved in cancer development. STAT1, STAT3 and STAT5 also possess tumour suppressive action in certain mutational and cancer type context. Here, we demonstrated member-specific STAT activity in major cancer types. Through systems biology approaches, we found surprising roles for EGFR family members, sex steroid hormone receptor ESR1 interplay with oncogenic STAT function and proposed new drug targeting approaches of oncogenic STAT pathway addiction.

GATA2 deficiency and MDS/AML: Experimental strategies for disease modelling and future therapeutic prospects.

The importance of predisposition to leukaemia in clinical practice is being increasingly recognized. This is emphasized by the establishment of a novel WHO disease category in 2016 called "myeloid neoplasms with germline predisposition". A major syndrome within this group is GATA2 deficiency, a heterogeneous immunodeficiency syndrome with a very high lifetime risk to develop myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). GATA2 deficiency has been identified as the most common hereditary cause of MDS in adolescents with monosomy 7. Allogenic haematopoietic stem cell transplantation is the only curative option; however, chances of survival decrease with progression of immunodeficiency and MDS evolution. Penetrance and expressivity within families carrying GATA2 mutations is often variable, suggesting that co-operating extrinsic events are required to trigger the disease. Predictive tools are lacking, and intrafamilial heterogeneity is poorly understood; hence there is a clear unmet medical need. On behalf of the ERAPerMed GATA2 HuMo consortium, in this review we describe the genetic, clinical, and biological aspects of familial GATA2-related MDS, highlighting the importance of developing robust disease preclinical models to improve early detection and clinical decision-making of GATA2 carriers.

Impact of the family communication environment on burden and clinical communication in blood cancer caregiving.

OBJECTIVE: We examined the effects of the family communication environment (conversation orientation) on adult child caregivers' burden and clinical interactions and if the effects are mediated by openness to communicate about cancer, avoidant cancer communication, and social support (SS). METHOD: Caregivers of a parent diagnosed with a blood cancer (N = 121) completed an online survey of validated measures of conversation orientation (i.e., the extent to which families openly communicate), SS, cancer openness, avoidance, caregiver burden, clinical communication skills, and quality of clinical interactions (QCI). RESULTS: Conversation orientation had significant indirect effects on caregiver burden, mediated by SS (ß = -0.11, p < 0.001), as well as cancer openness and avoidance (ß = -0.07, p < 0.001). Conversation orientation also had significant indirect effects on caregivers' communication skills with a parent's clinician, mediated by avoidance (ß = 0.08, p < 0.01) and SS (ß = 0.06, p < 0.001). Finally, conversation orientation had significant indirect effects on caregivers' QCI mediated by avoidance (ß = 0.71, p < 0.05). CONCLUSIONS: Adult child caregivers whose families communicate more openly exhibit less caregiver burden and report better clinical interaction skills and perceived quality of the clinical interaction. Avoidance emerged as a key mediating factor. Caregivers from less open communication environments may benefit from interventions that help them navigate challenging but critical caregiving conversations.

Living with or beyond lymphoma: A rapid review of the unmet needs of lymphoma survivors.

OBJECTIVE: To establish an understanding of the unmet needs of people living with or beyond a lymphoma diagnosis. Survivors of lymphoma are at increased risk of unmet needs due to cancer, treatment-related toxicities and extended survivorship. Despite the rapidly growing numbers of lymphoma survivors, their needs and research priorities are underserved and undervalued, therefore left largely unaddressed. METHODS: A rapid review method and reflexive thematic analysis approach assimilated current knowledge. Eligibility criteria included quantitative, qualitative, or mixed approaches employing cross-sectional, longitudinal, cohort or review designs focused on the needs of adult lymphoma survivors (any subtype or stage of disease). Five databases: CINAHL, EMBASE, Medline, PsycInfo and Scopus, were systematically searched. RESULTS: Forty-seven studies met the inclusion criteria via a stringent screening process facilitated by NVivo. Almost 60 per cent of articles were published within the last five years and investigated a homogenous lymphoma sample. Most studies employed quantitative approaches (77%) and cross-sectional designs (67%). Studies were of high methodological quality. Five major themes were identified: disparity in health service delivery, the psychological impact of cancer, impactful and debilitating concerns, the monetary cost of survival and insufficient provision of survivorship information. A meta-analytical approach was not feasible due to the breadth of methodologies of included studies. CONCLUSIONS: This review shows that lymphoma survivors experience a myriad of unmet needs across multiple domains, reinforcing the need for lymphoma-specific research. However, more research is needed to advance and achieve informed decision-making relating to survivorship care, placing due attention to the needs and research priorities of lymphoma survivors.

Looking beyond the cytogenetics in haematological malignancies: decoding the role of tandem repeats in DNA repair genes.

BACKGROUND: In cancer research, one of the most significant findings was to characterize the DNA repair deficiency as carcinogenic. Amongst the various repair mechanisms, mismatch repair (MMR) and direct reversal of DNA damage systems are designated as multilevel safeguards in the human genome. Defects in these elevate the rate of mutations and results in dire consequences like cancer. Of the several molecular signatures in human genome, tandem repeats (TRs) appear at various frequencies in the exonic, intronic, and regulatory regions of the DNA. Hypervariability among these repeats in the coding and non-coding regions of the genes is well characterized for solid tumours, but its significance in haematologic malignancies remains to be explored. The purpose of our study was to elucidate the role of nucleotide repeat instability in the coding and non-coding regions of 10 different repair genes in myeloid and lymphoid cell lines compared to the control samples. METHODS AND RESULTS: We selected MMR deficient extensively studied microsatellite instable colorectal cancer (HCT116), and MMR proficient breast cancer (MCF-7) cells along with underemphasized haematologic cancer cell lines to decipher the hypermutability of tandem repeats. A statistically significant TR variation was observed for MSH2 and MSH6 genes in 4 and 3 of the 6 cell lines respectively. KG1 (AML) and Daudi (Burkitt's lymphoma) were found to have compromised DNA repair competency with highly unstable nucleotide repeats. CONCLUSION: Taken together, the results suggest that mutable TRs in intronic and non-intronic regions of repair genes in blood cancer might have a tumorigenic role. Since this is a pilot study on cell lines, high throughput research in large cohorts can be undertaken to reveal novel diagnostic markers for unexplained blood cancer patients with normal karyotypes or otherwise with karyotypic defects.

Newly Synthesized Melphalan Analogs Induce DNA Damage and Mitotic Catastrophe in Hematological Malignant Cancer Cells.

Myeloablative therapy with highdoses of the cytostatic drug melphalan (MEL) in preparation for hematopoietic cell transplantation is the standard of care for multiple myeloma (MM) patients. Melphalan is a bifunctional alkylating agent that covalently binds to nucleophilic sites in the DNA and effective in the treatment, but unfortunately has limited therapeutic benefit. Therefore, new approaches are urgently needed for patients who are resistant to existing standard treatment with MEL. Regulating the pharmacological activity of drug molecules by modifying their structure is one method for improving their effectiveness. The purpose of this work was to analyze the physicochemical and biological properties of newly synthesized melphalan derivatives (EE-MEL, EM-MEL, EM-MOR-MEL, EM-I-MEL, EM-T-MEL) obtained through the esterification of the carboxyl group and the replacement of the the amino group with an amidine group. Compounds were selected based on our previous studies for their improved anticancer properties in comparison with the original drug. For this, we first evaluated the physicochemical properties using the circular dichroism technique, then analyzed the zeta potential and the hydrodynamic diameters of the particles. Then, the in vitro biological properties of the analogs were tested on multiple myeloma (RPMI8226), acute monocytic leukemia (THP1), and promyelocytic leukemia (HL60) cells as model systems for hematological malignant cells. DNA damage was assessed by immunostaining γH2AX, cell cycle distribution changes by propidium iodide (PI) staining, and cell death by the activation of caspase 2. We proved that the newly synthesized derivatives, in particular EM-MOR-MEL and EM-T-MEL, affected the B-DNA conformation, thus increasing the DNA damage. As a result of the DNA changes, the cell cycle was arrested in the S and G2/M phases. The cell death occurred by activating a mitotic catastrophe. Our investigations suggest that the analogs EM-MOR-MEL and EM-T-MEL have better anti-cancer activity in multiple myeloma cells than the currently used melphalan.

Heterochromatin and Polycomb as regulators of haematopoiesis.

Haematopoiesis is the process by which multipotent haematopoietic stem cells are transformed into each and every type of terminally differentiated blood cell. Epigenetic silencing is critical for this process by regulating the transcription of cell-cycle genes critical for self-renewal and differentiation, as well as restricting alternative fate genes to allow lineage commitment and appropriate differentiation. There are two distinct forms of transcriptionally repressed chromatin: H3K9me3-marked heterochromatin and H3K27me3/H2AK119ub1-marked Polycomb (often referred to as facultative heterochromatin). This review will discuss the role of these distinct epigenetic silencing mechanisms in regulating normal haematopoiesis, how these contribute to age-related haematopoietic dysfunction, and the rationale for therapeutic targeting of these pathways in the treatment of haematological malignancies.