1 6320 149 THE ROCKY ROAD TO PERSONALIZED MEDICINE IN ACUTE MYELOID LEUKAEMIA. ACUTE MYELOID LEUKAEMIA (AML) IS A MALIGNANT DISORDER OF THE MYELOID BLOOD LINEAGE CHARACTERIZED BY IMPAIRED DIFFERENTIATION AND INCREASED PROLIFERATION OF HEMATOPOIETIC PRECURSOR CELLS. RECENT TECHNOLOGICAL ADVANCES HAVE LED TO AN IMPROVED UNDERSTANDING OF AML BIOLOGY BUT ALSO UNCOVERED THE ENORMOUS CYTOGENETIC AND MOLECULAR HETEROGENEITY OF THE DISEASE. DESPITE THIS HETEROGENEITY, AML IS MOSTLY MANAGED BY A 'ONE-SIZE-FITS-ALL' APPROACH CONSISTING OF INTENSIVE, HIGHLY TOXIC INDUCTION AND CONSOLIDATION CHEMOTHERAPY. THESE TREATMENT PROTOCOLS HAVE REMAINED LARGELY UNCHANGED FOR THE PAST SEVERAL DECADES AND ONLY LEAD TO A CURE IN APPROXIMATELY 30-35% OF CASES. THE ADVENT OF TARGETED THERAPIES IN CHRONIC MYELOID LEUKAEMIA AND OTHER MALIGNANCIES HAS SPARKED HOPE TO IMPROVE PATIENT OUTCOME IN AML. HOWEVER, THE IMPLEMENTATION OF TARGETED AGENTS IN AML THERAPY HAS BEEN UNEXPECTEDLY CUMBERSOME AND REMAINS A DIFFICULT TASK DUE TO A VARIETY OF DISEASE- AND PATIENT-SPECIFIC FACTORS. IN THIS REVIEW, WE DESCRIBE CURRENT STANDARD AND INVESTIGATIONAL THERAPEUTIC STRATEGIES WITH A FOCUS ON TARGETED AGENTS AND HIGHLIGHT POTENTIAL TOOLS THAT MIGHT FACILITATE THE DEVELOPMENT OF TARGETED THERAPIES FOR THIS FATAL DISEASE. THE CLASSES OF AGENTS DESCRIBED IN THIS REVIEW INCLUDE CONSTITUTIVELY ACTIVATED SIGNALLING PATHWAY INHIBITORS, SURFACE RECEPTOR TARGETS, EPIGENETIC MODIFIERS, DRUGS TARGETING THE INTERACTION OF THE HEMATOPOIETIC PROGENITOR CELL WITH THE STROMA AND DRUGS THAT TARGET THE APOPTOTIC MACHINERY. THE CLINICAL CONTEXT AND OUTCOME WITH THESE AGENTS WILL BE EXAMINED TO GAIN INSIGHT ABOUT THEIR OPTIMAL UTILIZATION. 2018 2 6573 58 TREATMENT OF ACUTE MYELOID LEUKEMIA IN THE ERA OF GENOMICS-ACHIEVEMENTS AND PERSISTING CHALLENGES. ACUTE MYELOID LEUKEMIA (AML) REPRESENTS A MALIGNANT DISORDER OF THE HEMATOPOIETIC SYSTEM THAT IS MAINLY CHARACTERIZED BY RAPID PROLIFERATION, DYSREGULATED APOPTOSIS, AND IMPAIRED DIFFERENTIATION OF LEUKEMIC BLASTS. FOR SEVERAL DECADES, THE DIAGNOSTIC APPROACH IN AML WAS LARGELY BASED ON HISTOLOGIC CHARACTERISTICS WITH LITTLE IMPACT ON THE TREATMENT DECISION-MAKING PROCESS. THIS PERSPECTIVE HAS DRASTICALLY CHANGED WITHIN THE PAST YEARS DUE TO THE ADVENT OF NOVEL MOLECULAR TECHNOLOGIES, SUCH AS WHOLE GENOME NEXT-GENERATION SEQUENCING (NGS), AND THE RESULTING KNOWLEDGE GAIN IN AML BIOLOGY AND PATHOGENESIS. AFTER MORE THAN FOUR DECADES OF INTENSIVE CHEMOTHERAPY AS A "ONE-SIZE-FITS-ALL" CONCEPT, SEVERAL TARGETED AGENTS HAVE RECENTLY BEEN APPROVED FOR THE TREATMENT OF AML, EITHER AS SINGLE AGENTS OR AS PART OF COMBINED TREATMENT REGIMENS. SEVERAL OTHER COMPOUNDS, DIRECTED AGAINST REGULATORS OF APOPTOTIC, EPIGENETIC, OR MICROENVIRONMENTAL PATHWAYS, AS WELL AS MODULATORS OF THE IMMUNE SYSTEM, ARE CURRENTLY IN DEVELOPMENT AND BEING INVESTIGATED IN CLINICAL TRIALS. THE CONSTANT PROGRESS IN AML RESEARCH HAS STARTED TO PRODUCE IMPROVED SURVIVAL RATES AND FUELED HOPES THAT A ONCE RAPIDLY FATAL DISEASE CAN BE TRANSFORMED INTO A CHRONIC CONDITION. IN THIS REVIEW, THE AUTHORS PROVIDE A SUMMARY OF RECENT ADVANCES IN THE DEVELOPMENT OF TARGETED AML THERAPIES AND DISCUSS PERSISTENT CHALLENGES. 2020 3 3565 48 IMPACT OF GENETIC POLYMORPHISMS AND BIOMARKERS ON THE EFFECTIVENESS AND TOXICITY OF TREATMENT OF CHRONIC MYELOID LEUKEMIA AND ACUTE MYELOID LEUKEMIA. MOST MALIGNANT HEMATOLOGICAL DISEASES ARE GENERALLY A CONSEQUENCE OF ACQUIRED MUTATIONS OR REARRANGEMENTS IN CELL REPLICATION PROCESSES. ACUTE MYELOID LEUKEMIA (AML) IS A CLINICALLY AND MOLECULARLY HETEROGENEOUS DISEASE THAT RESULTS FROM ACQUIRED GENETIC AND EPIGENETIC ALTERATIONS IN HEMATOPOIETIC PROGENITOR CELLS. DESPITE THE ADVANCES MADE IN UNDERSTANDING THE PATHOGENESIS OF THIS DISEASE, THE OVERALL SURVIVAL OF PATIENTS REMAINS VERY LOW DUE TO THE HIGH RELAPSE RATE. PHARMACOGENETICS AND MASSIVE SEQUENCING STUDIES HAVE ALLOWED THE IDENTIFICATION OF NEW RECURRENT MUTATIONS WITH SIGNIFICANT PROGNOSTIC IMPACT IN AML; FURTHERMORE, IT SEEMS LIKELY THAT WHOLE GENOME SEQUENCING WILL SOON BECOME A STANDARD DIAGNOSTIC TEST, WHICH WILL ALLOW THE MOLECULAR DIAGNOSIS OF PATIENTS. THEREFORE, IT IS NECESSARY TO DEVELOP MOLECULAR TARGETS THAT OPEN NEW THERAPEUTIC PERSPECTIVES AND ALLOW INDIVIDUALIZED TREATMENT OF PATIENTS WITH THIS AGGRESSIVE DISEASE. CHRONIC MYELOID LEUKEMIA (CML) IS THE FIRST NEOPLASTIC DISEASE FOR WHICH A CHARACTERISTIC GENETIC ALTERATION WAS DESCRIBED. IT HAS, BY DEFINITION, A GENETIC MARKER, THE BCR::ABL1 REARRANGEMENT, AS A CONSEQUENCE OF THE T9;22(Q34;Q11) TRANSLOCATION. ITS STUDY IS ESSENTIAL FOR THE DIAGNOSIS OF THIS ENTITY AND ALSO FOR MONITORING THE RESPONSE TO TREATMENT. DRUGS KNOWN AS TYROSINE KINASE INHIBITORS (TKIS) THAT TARGET THE BCR::ABL1 PROTEIN (ORAL TARGETED THERAPY) ARE THE CONVENTIONAL TREATMENT OF CML, REPRESENTING A CHANGE OF PARADIGM IN THE MANAGEMENT OF ONCOHEMATOLOGICAL PATIENTS. 2022 4 1164 33 CONTRIBUTION OF CHRONIC MYELOID LEUKAEMIA (CML) AS A DISEASE MODEL TO DEFINE AND STUDY CLONAL HETEROGENEITY. ALTHOUGH TUMOUR CELL INTRA-CLONAL HETEROGENEITY HAS BEEN KNOWN FOR MANY YEARS, ITS APPLICATION IN THE ONCOLOGY CLINICAL PRACTICE (PATIENT MANAGEMENT, PROGNOSIS, ETC.) REMAINS LIMITED. FOR THIS, CHRONIC MYELOID LEUKAEMIA (CML) IS A REMARKABLE MODEL. BASIC RESEARCH STUDIES REVEALED THE HETEROGENEITY OF THE INITIAL CLONE, AND LED TO THE HYPOTHESIS OF THE EXISTENCE OF LEUKEMIC STEM CELLS. NEVERTHELESS, THE INDISPUTABLE EVIDENCE OF THE INTRA-CLONAL HETEROGENEITY ROLE IN THE THERAPEUTIC RESPONSE CAME FROM THE OUTCOMES OF THE TREATMENT WITH TYROSINE KINASE INHIBITORS (THE FIRST TARGETED THERAPY IN MEDICINE) COMBINED WITH THE EARLY AND RIGOROUS CLINICAL AND MOLECULAR MONITORING OF THESE PATIENTS. CML MANAGEMENT ALREADY TAKES THIS HETEROGENEITY INTO ACCOUNT FOR PERSONALIZED PATIENT FOLLOW-UP. THE ADVENTURE CONTINUES WITH THE OBJECTIVES OF BETTER TAILORING THE TREATMENT AND OF CURING THE DISEASE IN MOST OF THE PATIENTS. 2019 5 5913 40 TARGETED THERAPY IN LEUKEMIA. RESEARCH CONDUCTED OVER THE LAST TWO DECADES HAS YIELDED A DETAILED UNDERSTANDING OF THE MOLECULAR LESIONS THAT CONTRIBUTE TO THE MALIGNANT TRANSFORMATION OF HEMATOPOIETIC STEM CELLS AND COMMITTED PROGENITORS INTO THE VARIOUS FORMS OF ACUTE AND CHRONIC LEUKEMIA. ALTHOUGH OUR UNDERSTANDING OF THE MOLECULAR PATHOLOGY OF LEUKEMIA REMAINS INCOMPLETE, THE INFORMATION GAINED TO DATE HAS HAD A PROFOUND IMPACT ON THE WAY THESE MALIGNANCIES ARE BOTH DIAGNOSED AND MONITORED DURING THERAPY. MORE RECENTLY, TARGETED THERAPIES HAVE BEEN DEVELOPED AGAINST SOME OF THE IDENTIFIED GENETIC LESIONS. THESE THERAPIES HAVE LED TO SIGNIFICANT IMPROVEMENTS IN PATIENT OUTCOMES WHILE SIMULTANEOUSLY DECREASING THERAPY-RELATED TOXICITY. WITH THE ADVENT OF GENOME-WIDE METHODS TO DEFINE THE TOTAL COMPLEMENT OF GENETIC AND EPIGENETIC LESIONS INVOLVED IN LEUKEMOGENESIS, NEW TARGETED THERAPIES CAN BE ANTICIPATED. THIS REVIEW HIGHLIGHTS SOME OF THE TARGETED THERAPIES THAT ARE PRESENTLY BEING USED TO TREAT HEMATOPOIETIC MALIGNANCIES AND DESCRIBES SOME OF THE RECENT ADVANCES THAT SHOULD HAVE A SIGNIFICANT IMPACT ON THE DEVELOPMENT OF FUTURE TARGET THERAPIES. 2008 6 358 46 ALTERNATIVE SPLICING IN CHRONIC MYELOID LEUKEMIA (CML): A NOVEL THERAPEUTIC TARGET? ALTHOUGH THE IMATINIB BASED THERAPY OF CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS A TRIUMPH OF MEDICINE, NOT ALL PATIENTS WITH CML BENEFIT FROM THIS DRUG DUE TO THE DEVELOPMENT OF RESISTANCE AND INTOLERANCE. THE INTERRUPTION OF IMATINIB TREATMENT IS OFTEN FOLLOWED BY CLINICAL RELAPSE, SUGGESTING A FAILURE IN THE KILLING OF RESIDUAL LEUKAEMIC STEM CELLS. THERE IS NEED TO IDENTIFY ALTERNATIVE SELECTIVE MOLECULAR TARGETS FOR THIS DISEASE AND DEVELOP MORE EFFECTIVE THERAPEUTIC APPROACHES. ALTERNATIVE PRE-MRNA SPLICING (AS) IS AN EPIGENETIC PROCESS THAT GREATLY DIVERSIFIES THE REPERTOIRE OF THE TRANSCRIPTOME. AS ORCHESTRATES INTERACTIONS BETWEEN VARIOUS TYPES OF PROTEINS AND BETWEEN PROTEINS AND NUCLEIC ACIDS. CHANGES CAUSED BY INDIVIDUAL SPLICING EVENTS IN THE CELLS ARE SMALL, HOWEVER, "SPLICING PROGRAMS" TYPICALLY REACT TO THESE INDIVIDUAL CHANGES WITH CONSIDERABLE EFFECTS IN CELL PROLIFERATION, CELL SURVIVAL, AND APOPTOSIS. CURRENT EVIDENCE SUGGESTS A PIVOTAL ROLE OF AS IN LEUKEMIAS, PARTICULARLY IN MYELODISPLASTIC SYNDROME (MDS) AND CHRONIC LYMPHOCYTE LEUKEMIA (CLL). FROM THESE STUDIES AND STUDIES IN OTHER MALIGNANCES, IT IS CLEAR THAT SPLICING ABNORMALITIES PLAY A SIGNIFICANT ROLE IN MALIGNANT TRANSFORMATION. EVALUATION OF AS EVENTS IN CML CAN BE USED TO IDENTIFY NOVEL DISEASE MARKERS AND DRUGSENSITIVE TARGETS TO OVERCOME THE LIMITS OF THE SMALL MOLECULE INHIBITORS CURRENTLY USED FOR TREATING PATIENTS WITH CML. THE USE OF ABERRANT SPLICE VARIANTS AS DISEASE MARKERS HAS BEEN REPORTED, HOWEVER, LITTLE IS KNOWN ABOUT THE USE OF SPLICING ABNORMALITIES AS DRUG TARGETS IN CML. HEREIN WE DISCUSS POTENTIAL THERAPEUTIC APPROACHES THAT CAN BE USED TO TARGET SPLICING ABNORMALITIES IN CML. 2013 7 4681 37 NEW OPTIONS IN THE TREATMENT OF MYELODYSPLASTIC SYNDROME. MYELODYSPLASTIC SYNDROME (MDS) IS A HETEROGENEOUS GROUP OF PROGRESSIVE CHRONIC HEMATOPOIETIC DISORDERS, USUALLY PRESENTING AS REFRACTORY ANEMIA OR CYTOPENIA, WITH AN APPROXIMATELY 25% RISK OF PROGRESSION TOWARD ACUTE MYELOID LEUKAEIMA (AML), AND NO PROVEN CURATIVE TREATMENT. NOVEL BIOLOGICAL TREATMENT STRATEGIES TARGETING BOTH THE MALIGNANT BLOOD CELL AND ITS MICROENVIRONMENT CAN OVERCOME RESISTANCE TO CURRENT THERAPIES, AND REPRESENT A PROMISING TREATMENT PARADIGM FOR IMPROVING PATIENT OUTCOME. MANY OF THESE AGENTS HAVE MULTIPLE BIOLOGIC ACTIVITIES. THE OBJECTIVE OF THIS ARTICLE IS TO PRESENT A COMPARATIVE REVIEW OF CLASSIFICATION SYSTEMS IN MDS AND TO DISCUSS THE EVOLVING TRENDS IN THE TREATMENT OF MDS (IMMUNOSUPPRESIVE THERAPY, IMMUNOMODULATORY DRUGS, ARSENIC TRIOXIDE, PROTEASOME INHIBITORS, EPIGENETIC THERAPY). 2005 8 1882 37 EMERGING TREATMENTS IN ACUTE MYELOID LEUKAEMIA. ACUTE MYELOID LEUKAEMIA (AML) IS THE MOST COMMON FORM OF LEUKAEMIA IN YOUNG ADULTS. ALTHOUGH 75-85% OF PATIENTS WILL ACHIEVE COMPLETE REMISSION AFTER INDUCTION CHEMOTHERAPY, THE LONG-TERM SURVIVAL IS STILL < 50% AT 5 YEARS. CHEMOTHERAPY HAS INCREASED IN INTENSITY IN RECENT YEARS AND IS PERCEIVED TO HAVE REACHED THE LIMIT OF TOXICITY. ALLOGENEIC BONE MARROW TRANSPLANTATION, WHICH IS UNDOUBTEDLY THE MOST EFFECTIVE WAY TO PREVENT RELAPSE, MAY NOT ADD SUBSTANTIAL SURVIVAL BENEFITS. SEVERAL NEW PHARMACOLOGICAL APPROACHES TO THE TREATMENT OF AML ARE NOW BECOMING AVAILABLE, WITH VARIOUS MOLECULAR TARGETS IDENTIFIED, INCLUDING THE FARNESYLATION OF RAS FAMILY PROTEINS AND TYROSINE KINASES INVOLVED IN SIGNAL TRANSDUCTION AND EPIGENETIC METHYLATION. MORE SELECTIVE DELIVERY OF CHEMOTHERAPEUTIC AGENTS IS ALSO FEASIBLE USING HUMANISED MONOCLONAL ANTIBODIES, WITH THE INTRIGUING POSSIBILITY OF INCREASING TREATMENT DELIVERY WITHOUT INCREASING THE TOXICITY. HOWEVER, DESPITE THE PROGRESS IN THE RATIONAL DESIGN OF DRUGS IN DISORDERS SUCH AS CHRONIC MYELOID LEUKAEMIA, AML LACKS A SINGLE SPECIFIC PATHOGNOMIC GENETIC EVENT TO ACT AS A DRUG TARGET. THIS REVIEW DISCUSSES THE DRUGS PRESENTLY UNDER INVESTIGATION IN PHASE II OR PHASE III TRIALS IN AML. 2004 9 2652 37 EPIGENOMICS OF LEUKEMIA: FROM MECHANISMS TO THERAPEUTIC APPLICATIONS. LEUKEMOGENESIS IS A MULTISTEP PROCESS IN WHICH SUCCESSIVE TRANSFORMATIONAL EVENTS ENHANCE THE ABILITY OF A CLONAL POPULATION ARISING FROM HEMATOPOIETIC PROGENITOR CELLS TO PROLIFERATE, DIFFERENTIATE AND SURVIVE. CLINICALLY AND PATHOLOGICALLY, LEUKEMIA IS SUBDIVIDED INTO FOUR MAIN CATEGORIES: CHRONIC LYMPHOCYTIC LEUKEMIA, CHRONIC MYELOID LEUKEMIA, ACUTE LYMPHOCYTIC LEUKEMIA AND ACUTE MYELOID LEUKEMIA. LEUKEMIA HAS BEEN PREVIOUSLY CONSIDERED ONLY AS A GENETIC DISEASE. HOWEVER, IN RECENT YEARS, SIGNIFICANT ADVANCES HAVE BEEN MADE IN THE ELUCIDATION OF THE LEUKEMOGENESIS-ASSOCIATED PROCESSES. THUS, WE HAVE COME TO UNDERSTAND THAT EPIGENETIC ALTERATIONS INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND MIRNA ARE INVOLVED IN THE PERMANENT CHANGES OF GENE EXPRESSION CONTROLLING THE LEUKEMIA PHENOTYPE. IN THIS ARTICLE, WE WILL FOCUS ON THE EPIGENETIC DEFECTS ASSOCIATED WITH LEUKEMIA AND THEIR IMPLICATIONS AS BIOMARKERS FOR DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC APPLICATIONS. 2011 10 963 35 CHRONIC MYELOMONOCYTIC LEUKEMIA: INSIGHTS INTO BIOLOGY, PROGNOSTIC FACTORS, AND TREATMENT. PURPOSE OF REVIEW: CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOLOGICAL MALIGNANCY CHARACTERIZED BY BOTH DYSPLASTIC AND PROLIFERATIVE FEATURES, WITH AN INHERENT RISK FOR LEUKEMIC TRANSFORMATION. WITH THE HELP OF THIS REVIEW, WE AIM TO SUMMARIZE KEY CONCEPTS WITH REGARDS TO CMML BIOLOGY, DIAGNOSIS, RISK STRATIFICATION, AND THERAPEUTICS. RECENT FINDINGS: BASED ON RECENT STUDIES, CMML IS HALLMARKED BY A RELATIVELY LOW GENETIC COMPLEXITY, WHICH CONTRASTS WITH A COMPELLING PHENOTYPICAL HETEROGENEITY, LARGELY DRIVEN BY EPIGENETIC MECHANISMS. RECENT ADVANCES IN THE CHARACTERIZATION OF CMML BIOLOGY HAS LED TO AN IMPROVEMENT IN RISK-STRATIFICATION, BY MEANS OF INCORPORATING PROGNOSTICALLY RELEVANT GENE MUTATIONS. THIS, HOWEVER, HAS NOT SIGNIFICANTLY IMPACTED AVAILABLE THERAPIES AND OUTCOMES CONTINUE TO REMAIN POOR. ADVANCES IN CMML BIOLOGY HAVE BETTER EXPLAINED THE PHENOTYPIC HETEROGENEITY, WHILE CONTINUING TO DEFINE THE GENETIC AND EPIGENETIC LANDSCAPE. IN SPITE OF RECENT ADVANCES, LIMITED EFFECTIVE THERAPIES EXIST AND DEVELOPING RATIONALLY DERIVED THERAPEUTIC APPROACHES IS MUCH NEEDED. 2019 11 944 34 CHRONIC LYMPHOCYTIC LEUKEMIA: FROM MOLECULAR PATHOGENESIS TO NOVEL THERAPEUTIC STRATEGIES. CHRONIC LYMPHOCYTIC LEUKEMIA IS A WELL-DEFINED LYMPHOID NEOPLASM WITH VERY HETEROGENEOUS BIOLOGICAL AND CLINICAL BEHAVIOR. THE LAST DECADE HAS BEEN REMARKABLY FRUITFUL IN NOVEL FINDINGS ELUCIDATING MULTIPLE ASPECTS OF THE PATHOGENESIS OF THE DISEASE INCLUDING MECHANISMS OF GENETIC SUSCEPTIBILITY, INSIGHTS INTO THE RELEVANCE OF IMMUNOGENETIC FACTORS DRIVING THE DISEASE, PROFILING OF GENOMIC ALTERATIONS, EPIGENETIC SUBTYPES, GLOBAL EPIGENOMIC TUMOR CELL REPROGRAMMING, MODULATION OF TUMOR CELL AND MICROENVIRONMENT INTERACTIONS, AND DYNAMICS OF CLONAL EVOLUTION FROM EARLY STEPS IN MONOCLONAL B CELL LYMPHOCYTOSIS TO PROGRESSION AND TRANSFORMATION INTO DIFFUSE LARGE B-CELL LYMPHOMA. ALL THIS KNOWLEDGE HAS OFFERED NEW PERSPECTIVES THAT ARE BEING EXPLOITED THERAPEUTICALLY WITH NOVEL TARGET AGENTS AND MANAGEMENT STRATEGIES. IN THIS REVIEW WE PROVIDE AN OVERVIEW OF THESE NOVEL ADVANCES AND HIGHLIGHT QUESTIONS AND PERSPECTIVES THAT NEED FURTHER PROGRESS TO TRANSLATE INTO THE CLINICS THE BIOLOGICAL KNOWLEDGE AND IMPROVE THE OUTCOME OF THE PATIENTS. 2020 12 2393 42 EPIGENETIC REPROGRAMMING AND EMERGING EPIGENETIC THERAPIES IN CML. CHRONIC MYELOID LEUKEMIA (CML) IS A HEMATOPOIETIC STEM CELL DISORDER CHARACTERIZED BY BCR-ABL1, AN ONCOGENIC FUSION GENE ARISING FROM THE PHILADELPHIA CHROMOSOME. THE DEVELOPMENT OF TYROSINE KINASE INHIBITORS (TKIS) TO OVERCOME THE CONSTITUTIVE TYROSINE KINASE ACTIVITY OF THE BCR-ABL PROTEIN HAS DRAMATICALLY IMPROVED DISEASE MANAGEMENT AND PATIENT OUTCOMES OVER THE PAST 20 YEARS. HOWEVER, THE MAJORITY OF PATIENTS ARE NOT CURED AND DEVELOPING NOVEL THERAPEUTIC STRATEGIES THAT TARGET EPIGENETIC PROCESSES ARE A PROMISING AVENUE TO IMPROVE CURE RATES. A NUMBER OF EPIGENETIC MECHANISMS ARE ALTERED OR REPROGRAMMED DURING THE DEVELOPMENT AND PROGRESSION OF CML, RESULTING IN ALTERATIONS IN HISTONE MODIFICATIONS, DNA METHYLATION AND DYSREGULATION OF THE TRANSCRIPTIONAL MACHINERY. IN THIS REVIEW THESE EPIGENETIC ALTERATIONS ARE EXAMINED AND THE POTENTIAL OF EPIGENETIC THERAPIES ARE DISCUSSED AS A MEANS OF ERADICATING RESIDUAL DISEASE AND OFFERING A POTENTIAL CURE FOR CML IN COMBINATION WITH CURRENT THERAPIES. 2019 13 3651 39 INCREASING COMPLEXITY OF MOLECULAR LANDSCAPES IN HUMAN HEMATOPOIETIC STEM AND PROGENITOR CELLS DURING DEVELOPMENT AND AGING. THE PAST FIVE DECADES HAVE SEEN SIGNIFICANT PROGRESS IN OUR UNDERSTANDING OF HUMAN HEMATOPOIESIS. THIS HAS IN PART BEEN DUE TO THE UNPRECEDENTED DEVELOPMENT OF ADVANCED TECHNOLOGIES, WHICH HAVE ALLOWED THE IDENTIFICATION AND CHARACTERIZATION OF RARE SUBSETS OF HUMAN HEMATOPOIETIC STEM AND PROGENITOR CELLS AND THEIR LINEAGE TRAJECTORIES FROM EMBRYONIC THROUGH TO ADULT LIFE. ADDITIONALLY, SURROGATE IN VITRO AND IN VIVO MODELS, ALTHOUGH NOT FULLY RECAPITULATING HUMAN HEMATOPOIESIS, HAVE SPURRED ON THESE SCIENTIFIC ADVANCES. THESE APPROACHES HAVE HEIGHTENED OUR KNOWLEDGE OF HEMATOLOGICAL DISORDERS AND DISEASES AND HAVE LED TO THEIR IMPROVED DIAGNOSIS AND THERAPIES. HERE, WE REVIEW HUMAN HEMATOPOIESIS AT EACH END OF THE AGE SPECTRUM, DURING EMBRYONIC AND FETAL DEVELOPMENT AND ON AGING, PROVIDING EXEMPLARS OF RECENT PROGRESS IN DECIPHERING THE INCREASINGLY COMPLEX CELLULAR AND MOLECULAR HEMATOPOIETIC LANDSCAPES IN HEALTH AND DISEASE. THIS REVIEW CONCLUDES BY HIGHLIGHTING LINKS BETWEEN CHRONIC INFLAMMATION AND METABOLIC AND EPIGENETIC CHANGES ASSOCIATED WITH AGING AND IN THE DEVELOPMENT OF CLONAL HEMATOPOIESIS. 2022 14 6675 35 USING EPIGENETIC THERAPY TO OVERCOME CHEMOTHERAPY RESISTANCE. IT HAS BEEN KNOWN FOR DECADES THAT AS CANCER PROGRESSES, TUMORS DEVELOP GENETIC ALTERATIONS, MAKING THEM HIGHLY PRONE TO DEVELOPING RESISTANCE TO THERAPIES. CLASSICALLY, IT HAS BEEN THOUGHT THAT THESE ACQUIRED GENETIC CHANGES ARE FIXED. THIS HAS LED TO THE PARADIGM OF MOVING FROM ONE CANCER THERAPY TO THE NEXT WHILE AVOIDING PAST THERAPIES. HOWEVER, EMERGING DATA ON EPIGENETIC CHANGES DURING TUMOR PROGRESSION AND USE OF EPIGENETIC THERAPIES HAVE SHOWN THAT EPIGENETIC MODIFICATIONS LEADING TO CHEMOTHERAPY RESISTANCE HAVE THE POTENTIAL TO BE REVERSIBLE WITH EPIGENETIC THERAPY. IN FACT, PROMISING CLINICAL DATA EXIST THAT TREATMENT WITH EPIGENETIC AGENTS CAN DIMINISH CHEMOTHERAPY RESISTANCE IN A NUMBER OF TUMOR TYPES INCLUDING CHRONIC MYELOGENOUS LEUKEMIA, COLORECTAL, OVARIAN, LUNG AND BREAST CANCER. THE POTENTIAL FOR EPIGENETIC-MODIFYING DRUGS TO ALLOW FOR TREATMENT OF RESISTANT DISEASE IS EXCITING AND CLINICAL TRIALS HAVE JUST BEGUN TO EVALUATE THIS AREA. 2016 15 2085 47 EPIGENETIC DYSREGULATION IN CHRONIC MYELOID LEUKAEMIA: A MYRIAD OF MECHANISMS AND THERAPEUTIC OPTIONS. THE ONSET OF GLOBAL EPIGENETIC CHANGES IN CHROMATIN THAT DRIVE TUMOR PROLIFERATION AND HETEROGENEITY IS A HALLMARK OF MANY FORMS OF CANCER. IDENTIFYING THE EPIGENETIC MECHANISMS THAT GOVERN THESE CHANGES AND DEVELOPING THERAPEUTIC APPROACHES TO MODULATE THEM, IS A WELL-ESTABLISHED AVENUE PURSUED IN TRANSLATIONAL CANCER MEDICINE. CHRONIC MYELOID LEUKEMIA (CML) ARISES CLONALLY WHEN A HEMATOPOIETIC STEM CELL (HSC) ACQUIRES THE CAPACITY TO PRODUCE THE CONSTITUTIVELY ACTIVE TYROSINE KINASE BCR-ABL1 FUSION PROTEIN WHICH DRIVES TUMOR DEVELOPMENT. TREATMENT WITH TYROSINE KINASE INHIBITORS (TKI) THAT TARGET BCR-ABL1 HAS BEEN TRANSFORMATIVE IN CML MANAGEMENT BUT IT DOES NOT LEAD TO CURE IN THE VAST MAJORITY OF PATIENTS. THUS NOVEL THERAPEUTIC APPROACHES ARE REQUIRED AND THESE MUST TARGET CHANGES TO BIOLOGICAL PATHWAYS THAT ARE ABERRANT IN CML - INCLUDING THOSE THAT OCCUR WHEN EPIGENETIC MECHANISMS ARE ALTERED. THESE CHANGES MAY BE DUE TO ALTERATIONS IN DNA OR HISTONES, THEIR BIOCHEMICAL MODIFICATIONS AND REQUISITE 'WRITER' PROTEINS, OR TO DYSREGULATION OF VARIOUS TYPES OF NON-CODING RNAS THAT COLLECTIVELY FUNCTION AS MODULATORS OF TRANSCRIPTIONAL CONTROL AND DNA INTEGRITY. HERE, WE REVIEW THE EVIDENCE FOR SUBVERTED EPIGENETIC MECHANISMS IN CML AND HOW THESE IMPACT ON A DIVERSE SET OF BIOLOGICAL PATHWAYS, ON DISEASE PROGRESSION, PROGNOSIS AND DRUG RESISTANCE. WE WILL ALSO DISCUSS RECENT PROGRESS TOWARDS DEVELOPING EPIGENETIC THERAPIES THAT SHOW PROMISE TO IMPROVE CML PATIENT CARE AND MAY LEAD TO IMPROVED CURE RATES. 2018 16 4481 33 MOLECULAR PROFILING OF CHRONIC LYMPHOCYTIC LEUKAEMIA: GENETICS MEETS EPIGENETICS TO IDENTIFY PREDISPOSING GENES. MOLECULAR PROFILING MAY LEAD TO A BETTER UNDERSTANDING OF A DISEASE. THIS KNOWLEDGE IS ESPECIALLY IMPORTANT IN MALIGNANCIES, WHERE MULTIPLE ALTERATIONS ARE REQUIRED DURING THE PROGRESSION FROM PREMALIGNANT TO MALIGNANT STAGES. SUCH INFORMATION CAN BE USEFUL FOR THE DEVELOPMENT OF NOVEL BIOMARKERS THAT ALLOW THE PREDICTION OF A CLINICAL COURSE, RESPONSE TO TREATMENT OR EARLY DETECTION. MOLECULAR DATA IS ALSO UTILIZED TO DEVELOP TARGETED THERAPIES. MOREOVER, GENE DEFECTS IDENTIFIED IN PROFILING STUDIES WILL HELP TO UNDERSTAND THE MOLECULAR PATHWAYS DISRUPTED IN THE DISEASE. THIS REVIEW PROVIDES AN OVERVIEW OF MOLECULAR PROFILING APPROACHES IN CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL). WE WILL DESCRIBE OUR CURRENT UNDERSTANDING OF GENETIC ALTERATIONS IN CLL, THE USE OF FAMILIAL CLL FOR THE IDENTIFICATION OF PREDISPOSING MUTATIONS, AND THE SEARCH FOR EPIGENETIC ALTERATIONS IN CLL. 2007 17 4429 46 MOLECULAR BIOLOGY AS A TOOL FOR THE TREATMENT OF CANCER. CANCER IS A GENETIC DISEASE CHARACTERIZED BY UNCONTROLLED CELL GROWTH AND METASTASIS. CANCER CAN HAVE A NUMBER OF CAUSES, SUCH THE ACTIVATION OF ONCOGENES, THE INACTIVATION OF TUMOR-SUPPRESSING GENES, MUTAGENESIS PROVOKED BY EXTERNAL FACTORS, AND EPIGENETIC MODIFICATIONS. THE DEVELOPMENT OF DIAGNOSTIC TOOLS AND TREATMENTS USING A MOLECULAR BIOLOGICAL APPROACH PERMITS THE USE OF SENSITIVE, LOW-COST, NONINVASIVE TESTS FOR CANCER PATIENTS. BIOMARKERS CAN BE USED TO PROVIDE RAPID, PERSONALIZED ONCOLOGY, IN PARTICULAR THE MOLECULAR DIAGNOSIS OF CHRONIC MYELOID LEUKEMIA, AND GASTRIC, COLON, AND BREAST CANCERS. MOLECULAR TESTS BASED ON DNA METHYLATION CAN ALSO BE USED TO DIRECT TREATMENTS OR EVALUATE THE TOXIC EFFECTS OF CHEMOTHERAPY. THE ADEQUATE DIAGNOSIS, PROGNOSIS, AND PREDICTION OF THE RESPONSE OF CANCER PATIENTS TO TREATMENT ARE ESSENTIAL TO ENSURE THE MOST EFFECTIVE THERAPY, REDUCE THE DAMAGING EFFECTS OF TREATMENT, AND DIRECT THE THERAPY TO SPECIFIC TARGETS, AND IN THIS CONTEXT, MOLECULAR BIOLOGY HAS BECOME INCREASINGLY IMPORTANT IN ONCOLOGY. IN THIS BRIEF REVIEW, WE WILL DEMONSTRATE THE FUNDAMENTAL IMPORTANCE OF MOLECULAR BIOLOGY FOR THE TREATMENT OF THREE TYPES OF CANCER-CHRONIC MYELOID LEUKEMIA, HEREDITARY DIFFUSE GASTRIC CANCER, AND ASTROCYTOMAS (SPORADIC TUMORS OF THE CENTRAL NERVOUS SYSTEM). IN EACH OF THESE THREE MODELS, DISTINCT BIOLOGICAL MECHANISMS ARE INVOLVED IN THE TRANSFORMATION OF THE CELLS, BUT IN ALL CASES, MOLECULAR BIOLOGY IS FUNDAMENTAL TO THE DEVELOPMENT OF PERSONALIZED ANALYSES FOR EACH PATIENT AND EACH TYPE OF NEOPLASIA, AND TO GUARANTEE THE SUCCESS OF THE TREATMENT. 2018 18 109 46 A REVIEW ON THE THERAPEUTIC ROLE OF TKIS IN CASE OF CML IN COMBINATION WITH EPIGENETIC DRUGS. CHRONIC MYELOID LEUKEMIA IS A MALIGNANCY OF BONE MARROW THAT AFFECTS WHITE BLOOD CELLS. THERE IS STRONG EVIDENCE THAT DISEASE PROGRESSION, TREATMENT RESPONSES, AND OVERALL CLINICAL OUTCOMES OF CML PATIENTS ARE INFLUENCED BY THE ACCUMULATION OF OTHER GENETIC AND EPIGENETIC ABNORMALITIES, RATHER THAN ONLY THE BCR/ABL1 ONCOPROTEIN. BOTH GENETIC AND EPIGENETIC FACTORS INFLUENCE THE EFFICACY OF CML TREATMENT STRATEGIES. TARGETED MEDICINES KNOWN AS TYROSINE-KINASE INHIBITORS HAVE DRAMATICALLY IMPROVED LONG-TERM SURVIVAL RATES IN CML PATIENTS DURING THE PREVIOUS 2 DECADES. WHEN COMPARED TO EARLIER CHEMOTHERAPY TREATMENTS, THESE DRUGS HAVE REVOLUTIONIZED CML TREATMENT AND ALLOWED MOST PEOPLE TO LIVE LONGER LIVES. ALTHOUGH EPIGENETIC INHIBITORS' ACTIVITY IS DISRUPTED IN MANY CANCERS, INCLUDING CML, BUT WHEN COMBINED WITH TKI, THEY MAY OFFER POTENTIAL THERAPEUTIC STRATEGIES FOR THE TREATMENT OF CML CELLS. THE EPIGENETICS OF TYROSINE KINASE INHIBITORS AND RESISTANCE TO THEM IS BEING STUDIED, WITH A PARTICULAR FOCUS ON IMATINIB, WHICH IS USED TO TREAT CML. IN ADDITION, THE USE OF EPIGENETIC DRUGS IN CONJUNCTION WITH TKIS HAS BEEN DISCUSSED. RESISTANCE TO TKIS IS STILL A PROBLEM IN CURING THE DISEASE, NECESSITATING THE DEVELOPMENT OF NEW THERAPIES. THIS STUDY FOCUSED ON EPIGENETIC PATHWAYS INVOLVED IN CML PATHOGENESIS AND TUMOR CELL RESISTANCE TO TKIS, BOTH OF WHICH CONTRIBUTE TO LEUKEMIC CLONE BREAKOUT AND PROLIFERATION. 2021 19 2992 44 GENETIC LANDSCAPE AND DEREGULATED PATHWAYS IN B-CELL LYMPHOID MALIGNANCIES. WITH THE INTRODUCTION OF NEXT-GENERATION SEQUENCING, THE GENETIC LANDSCAPE OF THE COMPLEX GROUP OF B-CELL LYMPHOID MALIGNANCIES HAS RAPIDLY BEEN UNRAVELLED IN RECENT YEARS. THIS HAS PROVIDED IMPORTANT INFORMATION ABOUT RECURRENT GENETIC EVENTS AND IDENTIFIED KEY PATHWAYS DEREGULATED IN EACH LYMPHOMA SUBTYPE. IN PARALLEL, THERE HAS BEEN INTENSE SEARCH AND DEVELOPMENT OF NOVEL TYPES OF TARGETED THERAPY THAT 'HIT' CENTRAL MECHANISMS IN LYMPHOMA PATHOBIOLOGY, SUCH AS BTK, PI3K OR BCL2 INHIBITORS. IN THIS REVIEW, WE WILL OUTLINE THE CURRENT VIEW OF THE GENETIC LANDSCAPE OF SELECTED ENTITIES: FOLLICULAR LYMPHOMA, DIFFUSE LARGE B-CELL LYMPHOMA, MANTLE CELL LYMPHOMA, CHRONIC LYMPHOCYTIC LEUKAEMIA AND MARGINAL ZONE LYMPHOMA. WE WILL DETAIL RECURRENT ALTERATIONS AFFECTING IMPORTANT SIGNALLING PATHWAYS, THAT IS THE B-CELL RECEPTOR/NF-KAPPAB PATHWAY, NOTCH SIGNALLING, JAK-STAT SIGNALLING, P53/DNA DAMAGE RESPONSE, APOPTOSIS AND CELL CYCLE REGULATION, AS WELL AS OTHER PERHAPS UNEXPECTED CELLULAR PROCESSES, SUCH AS IMMUNE REGULATION, CELL MIGRATION, EPIGENETIC REGULATION AND RNA PROCESSING. WHILST MANY OF THESE PATHWAYS/PROCESSES ARE COMMONLY ALTERED IN DIFFERENT LYMPHOID TUMORS, ALBEIT AT VARYING FREQUENCIES, OTHERS ARE PREFERENTIALLY TARGETED IN SELECTED B-CELL MALIGNANCIES. SOME OF THESE GENETIC LESIONS ARE EITHER INVOLVED IN DISEASE ONTOGENY OR LINKED TO THE EVOLUTION OF EACH DISEASE AND/OR SPECIFIC CLINICOBIOLOGICAL FEATURES, AND SOME OF THEM HAVE BEEN DEMONSTRATED TO HAVE PROGNOSTIC AND EVEN PREDICTIVE IMPACT. FUTURE WORK IS ESPECIALLY NEEDED TO UNDERSTAND THE THERAPY-RESISTANT DISEASE, PARTICULARLY IN PATIENTS TREATED WITH TARGETED THERAPY, AND TO IDENTIFY NOVEL TARGETS AND THERAPEUTIC STRATEGIES IN ORDER TO REALIZE TRUE PRECISION MEDICINE IN THIS CLINICALLY HETEROGENEOUS PATIENT GROUP. 2017 20 937 24 CHRONIC LYMPHOCYTIC LEUKAEMIA GENOMICS AND THE PRECISION MEDICINE ERA. MASSIVE GENOMIC ANALYSES HAVE UNDERSCORED THE DIVERSITY OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) BETWEEN PATIENTS. GENETIC HETEROGENEITY OF TUMOUR CLONES WITHIN A PATIENT MAY FUEL TUMOUR EVOLUTION. SEVERAL RECURRENTLY DEREGULATED INTRA-CELLULAR PATHWAYS ARE CANDIDATES FOR TARGETED THERAPIES THAT ARE VERY PROMISING AND ARE DRAMATICALLY CHANGING CLINICAL PATIENTS' PERSPECTIVES. IN THIS REVIEW WE PRESENT AN OVERVIEW OF THE GENETIC AND EPIGENETIC FEATURES OF CLL AND THEIR CLINICAL AND BIOLOGICAL IMPLICATIONS. 2017