1 4760 161 NOVEL TREATMENTS OF ADULT T CELL LEUKEMIA LYMPHOMA. ADULT T CELL LEUKEMIA-LYMPHOMA (ATL) IS AN AGGRESSIVE MALIGNANCY SECONDARY TO CHRONIC INFECTION WITH THE HUMAN T CELL LEUKEMIA VIRUS TYPE I (HTLV-I) RETROVIRUS. ATL CARRIES A DISMAL PROGNOSIS. ATL CLASSIFIES INTO FOUR SUBTYPES (ACUTE, LYMPHOMA, CHRONIC, AND SMOLDERING) WHICH DISPLAY DIFFERENT CLINICAL FEATURES, PROGNOSIS AND RESPONSE TO THERAPY, HENCE REQUIRING DIFFERENT CLINICAL MANAGEMENT. SMOLDERING AND CHRONIC SUBTYPES RESPOND WELL TO ANTIRETROVIRAL THERAPY USING THE COMBINATION OF ZIDOVUDINE (AZT) AND INTERFERON-ALPHA (IFN) WITH A SIGNIFICANT PROLONGATION OF SURVIVAL. CONVERSELY, THE WATCH AND WAIT STRATEGY OR CHEMOTHERAPY FOR THESE INDOLENT SUBTYPES ALLIES WITH A POOR LONG-TERM OUTCOME. ACUTE ATL IS ASSOCIATED WITH CHEMO-RESISTANCE AND DISMAL PROGNOSIS. LYMPHOMA SUBTYPES RESPOND BETTER TO INTENSIVE CHEMOTHERAPY BUT SURVIVAL REMAINS POOR. ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) RESULTS IN LONG-TERM SURVIVAL IN ROUGHLY ONE THIRD OF TRANSPLANTED PATIENTS BUT ONLY A SMALL PERCENTAGE OF PATIENTS CAN MAKE IT TO TRANSPLANT. OVERALL, CURRENT TREATMENTS OF AGGRESSIVE ATL ARE NOT SATISFACTORY. PROGNOSIS OF REFRACTORY OR RELAPSED PATIENTS IS DISMAL WITH SOME ENCOURAGING RESULTS WHEN USING LENALIDOMIDE OR MOGAMULIZUMAB. TO OVERCOME RESISTANCE AND PREVENT RELAPSE, PRECLINICAL OR PILOT CLINICAL STUDIES USING TARGETED THERAPIES SUCH AS ARSENIC/IFN, MONOCLONAL ANTIBODIES, EPIGENETIC THERAPIES ARE PROMISING BUT WARRANT FURTHER CLINICAL INVESTIGATION. ANTI-ATL VACCINES INCLUDING TAX PEPTIDE-PULSED DENDRITIC CELLS, INDUCED TAX-SPECIFIC CTL RESPONSES IN ATL PATIENTS. FINALLY, BASED ON THE PROGRESS IN UNDERSTANDING THE PATHOPHYSIOLOGY OF ATL, AND THE RISK-ADAPTED TREATMENT APPROACHES TO DIFFERENT ATL SUBTYPES, TREATMENT STRATEGIES OF ATL SHOULD TAKE INTO ACCOUNT THE HOST IMMUNE RESPONSES AND THE HOST MICROENVIRONMENT INCLUDING HTLV-1 INFECTED NON-MALIGNANT CELLS. HEREIN, WE WILL PROVIDE A SUMMARY OF NOVEL TREATMENTS OF ATL IN VITRO, IN VIVO, AND IN EARLY CLINICAL TRIALS. 2020 2 4951 25 PATHOGENESIS OF CHOLANGIOCARCINOMA: FROM GENETICS TO SIGNALLING PATHWAYS. CHOLANGIOCARCINOMA (CCA) IS A MALIGNANT TUMOUR OF BILE DUCT EPITHELIAL CELLS WITH DISMAL PROGNOSIS AND RISING INCIDENCE. CHRONIC INFLAMMATION RESULTING FROM LIVER FLUKE INFECTION, HEPATITIS AND OTHER INFLAMMATORY BOWEL DISEASES IS A MAJOR CONTRIBUTING FACTOR TO CHOLANGIOCARCINOGENESIS, LIKELY THROUGH ACCUMULATION OF SERIAL GENETIC AND EPIGENETIC ALTERATIONS RESULTING IN ABERRATION OF ONCOGENES AND TUMOUR SUPPRESSORS. RECENT STUDIES MAKING USE OF ADVANCES IN HIGH-THROUGHPUT GENOMICS HAVE REVEALED THE GENETIC LANDSCAPE OF CCA, GREATLY INCREASING OUR UNDERSTANDING OF ITS UNDERLYING BIOLOGY. A SERIES OF HIGHLY RECURRENT MUTATIONS IN GENES SUCH AS TP53, KRAS, SMAD4, BRAF, MLL3, ARID1A, PBRM1 AND BAP1, WHICH ARE KNOWN TO BE INVOLVED IN CELL CYCLE CONTROL, CELL SIGNALLING PATHWAYS AND CHROMATIN DYNAMICS, HAVE LED TO INVESTIGATIONS OF THEIR ROLES, THROUGH MOLECULAR TO MOUSE MODELLING STUDIES, IN CHOLANGIOCARCINOGENESIS. THIS REVIEW FOCUSES ON THE LANDSCAPE GENETIC ALTERATIONS IN CCA AND ITS FUNCTIONAL RELEVANCE TO THE FORMATION AND PROGRESSION OF CCA. 2015 3 791 35 CELLULAR AND MOLECULAR NETWORKS IN CHRONIC MYELOID LEUKEMIA: THE LEUKEMIC STEM, PROGENITOR AND STROMAL CELL INTERPLAY. THE USE OF IMATINIB, SECOND AND THIRD GENERATION ABL TYROSINE KINASE INHIBITORS (TKI) (I.E. DASATINIB, NILOTINIB, BOSUTINIB AND PONATINIB) MADE CML A CLINICALLY MANAGEABLE AND, IN A SMALL PERCENTAGE OF CASES, A CURED DISEASE. TKI THERAPY ALSO TURNED CML BLASTIC TRANSFORMATION INTO A RARE EVENT; HOWEVER, DISEASE PROGRESSION STILL OCCURS IN THOSE PATIENTS WHO ARE REFRACTORY, NOT COMPLIANT WITH TKI THERAPY OR DEVELOP RESISTANCE TO MULTIPLE TKIS. IN THE PAST FEW YEARS, IT BECAME CLEAR THAT THE BCRABL1 ONCOGENE DOES NOT OPERATE ALONE TO DRIVE DISEASE EMERGENCE, MAINTENANCE AND PROGRESSION. INDEED, IT SEEMS THAT BONE MARROW (BM) MICROENVIRONMENT-GENERATED SIGNALS AND CELL AUTONOMOUS BCRABL1 KINASE-INDEPENDENT GENETIC AND EPIGENETIC ALTERATIONS ALL CONTRIBUTE TO: I. PERSISTENCE OF A QUIESCENT LEUKEMIC STEM CELL (LSC) RESERVOIR, II. INNATE OR ACQUIRED RESISTANCE TO TKIS, AND III. PROGRESSION INTO THE FATAL BLAST CRISIS STAGE. HEREIN, WE REVIEW THE INTRICATE LEUKEMIC NETWORK IN WHICH ABERRANT, BUT FINELY TUNED, SURVIVAL, MITOGENIC AND SELF-RENEWAL SIGNALS ARE GENERATED BY LEUKEMIC PROGENITORS, STROMAL CELLS, IMMUNE CELLS AND METABOLIC MICROENVIRONMENTAL CONDITIONS (E.G. HYPOXIA) TO PROMOTE LSC MAINTENANCE AND BLASTIC TRANSFORMATION. 2017 4 953 35 CHRONIC MYELOID LEUKEMIA STEM CELLS. ALTHOUGH RARE, CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS AN IMPORTANT PARADIGM FOR UNDERSTANDING THE MOLECULAR EVENTS LEADING TO MALIGNANT TRANSFORMATION OF PRIMITIVE HEMATOPOIETIC PROGENITORS. CML WAS THE FIRST CANCER TO BE ASSOCIATED WITH A DEFINED GENETIC ABNORMALITY, BCR-ABL, THAT IS NECESSARY AND SUFFICIENT FOR INITIATING CHRONIC PHASE DISEASE AS WELL AS THE FIRST CANCER TO BE TREATED WITH MOLECULAR TARGETED THERAPY. MALIGNANT PROGENITORS OR LEUKEMIA STEM CELLS (LSCS) EVOLVE AS A RESULT OF BOTH EPIGENETIC AND GENETIC EVENTS THAT ALTER HEMATOPOIETIC PROGENITOR DIFFERENTIATION, PROLIFERATION, SURVIVAL, AND SELF-RENEWAL. LSCS ARE RARE AND DIVIDE LESS FREQUENTLY, AND THUS, REPRESENT A RESERVOIR FOR RELAPSE AND RESISTANCE TO A MOLECULARLY TARGETED SINGLE AGENT. ON SUBVERTING DEVELOPMENTAL PROCESSES NORMALLY RESPONSIBLE FOR MAINTAINING ROBUST LIFE-LONG HEMATOPOIESIS, THE LSCS ARE ABLE TO EVADE THE MAJORITY OF CURRENT CANCER TREATMENTS THAT TARGET RAPIDLY DIVIDING CELLS. ENTHUSIASM FOR THE ENORMOUS SUCCESS OF TYROSINE KINASE INHIBITORS AT CONTROLLING THE CHRONIC PHASE DISEASE IS TEMPERED SOMEWHAT BY THE PERSISTENCE OF THE LSC POOL IN THE MAJORITY OF THE PATIENTS. COMBINED THERAPIES TARGETING ABERRANT PROPERTIES OF LSC MAY OBVIATE THERAPEUTIC RESISTANCE AND RELAPSE IN ADVANCED PHASE AND THERAPEUTICALLY RECALCITRANT CML. 2008 5 6271 32 THE ONCOGENIC ROLE OF HEPATITIS B VIRUS. THE HEPATITIS B VIRUS (HBV) IS A SMALL ENVELOPED DNA VIRUS THAT CAUSES ACUTE AND CHRONIC HEPATITIS. HBV INFECTION IS A WORLD HEALTH PROBLEM, WITH 350 MILLION CHRONICALLY INFECTED PEOPLE AT INCREASED RISK OF DEVELOPING LIVER DISEASE AND HEPATOCELLULAR CARCINOMA (HCC). HBV HAS BEEN CLASSIFIED AMONG HUMAN TUMOR VIRUSES BY VIRTUE OF A ROBUST EPIDEMIOLOGIC ASSOCIATION BETWEEN CHRONIC HBV CARRIAGE AND HCC OCCURRENCE. IN THE ABSENCE OF CYTOPATHIC EFFECT IN INFECTED HEPATOCYTES, THE ONCOGENIC ROLE OF HBV MIGHT INVOLVE A COMBINATION OF DIRECT AND INDIRECT EFFECTS OF THE VIRUS DURING THE MULTISTEP PROCESS OF LIVER CARCINOGENESIS. LIVER INFLAMMATION AND HEPATOCYTE PROLIFERATION DRIVEN BY HOST IMMUNE RESPONSES ARE RECOGNIZED DRIVING FORCES OF LIVER CELL TRANSFORMATION. GENETIC AND EPIGENETIC ALTERATIONS CAN ALSO RESULT FROM VIRAL DNA INTEGRATION INTO HOST CHROMOSOMES AND FROM PROLONGED EXPRESSION OF VIRAL GENE PRODUCTS. NOTABLY, THE TRANSCRIPTIONAL REGULATORY PROTEIN HBX ENCODED BY THE X GENE IS ENDOWED WITH TUMOR PROMOTER ACTIVITY. HBX HAS PLEIOTROPIC ACTIVITIES AND PLAYS A MAJOR ROLE IN HBV PATHOGENESIS AND IN LIVER CARCINOGENESIS. BECAUSE HEPATIC TUMORS CARRY A DISMAL PROGNOSIS, THERE IS URGENT NEED TO DEVELOP EARLY DIAGNOSTIC MARKERS OF HCC AND EFFECTIVE THERAPIES AGAINST CHRONIC HEPATITIS B. DECIPHERING THE ONCOGENIC MECHANISMS THAT UNDERLIE HBV-RELATED TUMORIGENESIS MIGHT HELP DEVELOPING ADAPTED THERAPEUTIC STRATEGIES. 2014 6 4474 40 MOLECULAR PATHOGENESIS OF GALLBLADDER CANCER: AN UPDATE. GALLBLADDER CARCINOMA (GBC) IS THE MOST AGGRESSIVE GASTROINTESTINAL MALIGNANCY THROUGHOUT THE WORLD, WITH WIDE GEOGRAPHICAL VARIANCE. IT IS THE SUBTYPE OF BILIARY TRACT MALIGNANCY THAT HAS THE POOREST PROGNOSIS AND LOWER SURVIVAL AMONG ALL BILIARY TRACT MALIGNANCIES. VARIOUS FACTORS ARE ASSOCIATED WITH GBC PATHOGENESIS SUCH AS ENVIRONMENTAL, MICROBIAL, METABOLIC AND MOLECULAR. CHRONIC INFLAMMATION OF GALLBLADDER DUE TO PRESENCE OF GALLSTONE OR MICROBIAL INFECTION (EG. SALMONELLA OR H. PYLORI) RESULTS IN SUSTAINED PRODUCTION OF INFLAMMATORY MEDIATORS IN THE TISSUE MICROENVIRONMENT, WHICH CAN CAUSE GENOMIC CHANGES LINKED TO CARCINOGENESIS. GENETIC ALTERATIONS ARE ONE OF THE MAJOR FACTORS, ASSOCIATED WITH AGGRESSIVENESS AND PROGNOSIS. RESEARCHES HAVE BEEN DONE TO EXPLORE SUITABLE BIOMARKER FOR EARLY DIAGNOSIS AND IDENTIFY ALTERED MOLECULAR PATHWAYS TO DEVELOP APPROPRIATE BIOMARKERS FOR EARLY DIAGNOSIS, THERAPY AND PREDICTING PROGNOSIS. DIFFERENT AGENTS FOR TARGETED THERAPY AGAINST ACTIONABLE MUTATIONS OF MOLECULES LIKE EGFR, VEGF, MTOR, HER2, PDL-1, PD-1, MET, PI3K, N-CADHERIN, VEGFR, MEK1 AND MEK2 ARE BEING TRIED. DESPITE THESE ADVANCEMENTS, THERE IS DISMAL IMPROVEMENT IN THE SURVIVAL OF GBC PATIENTS. GENETIC ABERRATIONS OTHER THAN ACTIONABLE MUTATIONS AND EPIGENETIC MODIFICATION INCLUDING ABERRANT EXPRESSIONS OF MICRO-RNAS, ARE ALSO BEING STUDIED BOTH AS DIAGNOSTIC BIOMARKER AND THERAPEUTIC TARGETS. COMPLEX PATHOGENESIS OF GBC STILL NEEDS TO BE UNFOLDED. IN THIS REVIEW WE FOCUS ON THE MOLECULAR PATHOGENESIS OF GBC ELUCIDATED TILL DATE ALONG WITH FUTURE DIRECTIONS THAT CAN BE EXPLORED TO ACHIEVE BETTER MANAGEMENT OF GBC PATIENTS. 2019 7 952 34 CHRONIC MYELOID LEUKEMIA STEM CELL BIOLOGY. LEUKEMIA PROGRESSION AND RELAPSE IS FUELED BY LEUKEMIA STEM CELLS (LSC) THAT ARE RESISTANT TO CURRENT TREATMENTS. IN THE PROGRESSION OF CHRONIC MYELOID LEUKEMIA (CML), BLAST CRISIS PROGENITORS ARE CAPABLE OF ADOPTING MORE PRIMITIVE BUT DEREGULATED STEM CELL FEATURES WITH ACQUIRED RESISTANCE TO TARGETED THERAPIES. THIS IN TURN PROMOTES LSC BEHAVIOR CHARACTERIZED BY ABERRANT SELF-RENEWAL, DIFFERENTIATION, AND SURVIVAL CAPACITY. MULTIPLE REPORTS SUGGEST THAT CELL CYCLE ALTERATIONS, ACTIVATION OF CRITICAL SIGNALING PATHWAYS, ABERRANT MICROENVIRONMENTAL CUES FROM THE HEMATOPOIETIC NICHE, AND ABERRANT EPIGENETIC EVENTS AND DEREGULATION OF RNA PROCESSING MAY FACILITATE THE ENHANCED SURVIVAL AND MALIGNANT TRANSFORMATION OF CML PROGENITORS. HERE WE REVIEW THE MOLECULAR EVOLUTION OF CML LSC THAT PROMOTES CML PROGRESSION AND RELAPSE. RECENT ADVANCES IN THESE AREAS HAVE IDENTIFIED NOVEL TARGETS THAT REPRESENT IMPORTANT AVENUES FOR FUTURE THERAPEUTIC APPROACHES AIMED AT SELECTIVELY ERADICATING THE LSC POPULATION WHILE SPARING NORMAL HEMATOPOIETIC PROGENITORS IN PATIENTS SUFFERING FROM CHRONIC MYELOID MALIGNANCIES. 2012 8 4124 38 MECHANISMS OF DISEASE PROGRESSION AND RESISTANCE TO TYROSINE KINASE INHIBITOR THERAPY IN CHRONIC MYELOID LEUKEMIA: AN UPDATE. CHRONIC MYELOID LEUKEMIA (CML) IS CHARACTERIZED BY THE PRESENCE OF THE BCR-ABL1 FUSION GENE, WHICH ENCODES A CONSTITUTIVE ACTIVE TYROSINE KINASE CONSIDERED TO BE THE PATHOGENIC DRIVER CAPABLE OF INITIATING AND MAINTAINING THE DISEASE. DESPITE THE REMARKABLE EFFICACY OF TYROSINE KINASE INHIBITORS (TKIS) TARGETING BCR-ABL1, SOME PATIENTS MAY NOT RESPOND (PRIMARY RESISTANCE) OR MAY RELAPSE AFTER AN INITIAL RESPONSE (SECONDARY RESISTANCE). IN A SMALL PROPORTION OF CASES, DEVELOPMENT OF RESISTANCE IS ACCOMPANIED OR SHORTLY FOLLOWED BY PROGRESSION FROM CHRONIC TO BLASTIC PHASE (BP), CHARACTERIZED BY A DISMAL PROGNOSIS. EVOLUTION FROM CP INTO BP IS A MULTIFACTORIAL AND PROBABLY MULTISTEP PHENOMENON. INCREASE IN BCR-ABL1 TRANSCRIPT LEVELS IS THOUGHT TO PROMOTE THE ONSET OF SECONDARY CHROMOSOMAL OR GENETIC DEFECTS, INDUCE DIFFERENTIATION ARREST, PERTURB RNA TRANSCRIPTION, EDITING AND TRANSLATION THAT TOGETHER WITH EPIGENETIC AND METABOLIC CHANGES MAY ULTIMATELY LEAD TO THE EXPANSION OF HIGHLY PROLIFERATING, DIFFERENTIATION-ARRESTED MALIGNANT CELLS. A MULTITUDE OF STUDIES OVER THE PAST TWO DECADES HAVE INVESTIGATED THE MECHANISMS UNDERLYING THE CLOSELY INTERTWINED PHENOMENA OF DRUG RESISTANCE AND DISEASE PROGRESSION. HERE, WE PROVIDE AN UPDATE ON WHAT IS CURRENTLY KNOWN ON THE MECHANISMS UNDERLYING PROGRESSION AND PRESENT THE LATEST ACQUISITIONS ON BCR-ABL1-INDEPENDENT RESISTANCE AND LEUKEMIA STEM CELL PERSISTENCE. 2019 9 6618 39 UNDERSTANDING AND MONITORING CHRONIC MYELOID LEUKEMIA BLAST CRISIS: HOW TO BETTER MANAGE PATIENTS. CHRONIC MYELOID LEUKEMIA (CML) IS TRIGGERED PRIMARILY BY THE T(9;22) (Q34.13; Q11.23) TRANSLOCATION. THIS RECIPROCAL CHROMOSOMAL TRANSLOCATION LEADS TO THE FORMATION OF THE BCR-ABL FUSION GENE. PATIENTS IN THE CHRONIC PHASE (CP) EXPERIENCE A GOOD CURATIVE EFFECT WITH TYROSINE KINASE INHIBITORS. HOWEVER, CASES ARE TREATMENT REFRACTORY, WITH A DISMAL PROGNOSIS, WHEN THE DISEASE HAS PROGRESSED TO THE ACCELERATED PHASE (AP) OR BLAST PHASE (BP). UNTIL NOW, FEW REPORTS HAVE PROVIDED A COMPREHENSIVE DESCRIPTION OF THE MECHANISMS INVOLVED AT DIFFERENT MOLECULAR LEVELS. INDEED, THE UNDERLYING PATHOGENESIS OF CML EVOLUTION COMPRISES GENETIC ABERRATIONS, CHROMOSOMAL TRANSLOCATIONS (EXCEPT FOR THE PHILADELPHIA CHROMOSOME), TELOMERE BIOLOGY, AND EPIGENETIC ANOMALIES. HEREIN, WE PROVIDE KNOWLEDGE OF THE BIOLOGY RESPONSIBLE FOR BLAST TRANSFORMATION OF CML AT SEVERAL LEVELS, SUCH AS GENETICS, TELOMERE BIOLOGY, AND EPIGENETIC ANOMALIES. BECAUSE OF THE LIMITED TREATMENT OPTIONS AVAILABLE AND POOR OUTCOMES, ONLY THE THERAPEUTIC RESPONSE IS MONITORED REGULARLY, WHICH INVOLVES BCR-ABL TRANSCRIPT LEVEL ASSESSMENT AND IMMUNOLOGIC SURVEILLANCE, WITH THE OPTIMAL TREATMENT STRATEGY FOR PATIENTS IN CP ADAPTED TO EVALUATE DISEASE RECURRENCE OR PROGRESSION. OVERALL, SELECTING OPTIMAL TREATMENT ENDPOINTS TO PREDICT SURVIVAL AND SUCCESSFUL TFR IMPROVES THE QUALITY OF LIFE OF PATIENTS. THUS, IDENTIFYING RISK FACTORS AND DEVELOPING RISK-ADAPTED THERAPEUTIC OPTIONS MAY CONTRIBUTE TO A BETTER OUTCOME FOR ADVANCED-PHASE PATIENTS. 2021 10 955 30 CHRONIC MYELOID LEUKEMIA: MECHANISMS OF BLASTIC TRANSFORMATION. THE BCR-ABL1 ONCOPROTEIN TRANSFORMS PLURIPOTENT HSCS AND INITIATES CHRONIC MYELOID LEUKEMIA (CML). PATIENTS WITH EARLY PHASE (ALSO KNOWN AS CHRONIC PHASE [CP]) DISEASE USUALLY RESPOND TO TREATMENT WITH ABL TYROSINE KINASE INHIBITORS (TKIS), ALTHOUGH SOME PATIENTS WHO RESPOND INITIALLY LATER BECOME RESISTANT. IN MOST PATIENTS, TKIS REDUCE THE LEUKEMIA CELL LOAD SUBSTANTIALLY, BUT THE CELLS FROM WHICH THE LEUKEMIA CELLS ARE DERIVED DURING CP (SO-CALLED LEUKEMIA STEM CELLS [LSCS]) ARE INTRINSICALLY INSENSITIVE TO TKIS AND SURVIVE LONG TERM. LSCS OR THEIR PROGENY CAN ACQUIRE ADDITIONAL GENETIC AND/OR EPIGENETIC CHANGES THAT CAUSE THE LEUKEMIA TO TRANSFORM FROM CP TO A MORE ADVANCED PHASE, WHICH HAS BEEN SUBCLASSIFIED AS EITHER ACCELERATED PHASE OR BLASTIC PHASE DISEASE. THE LATTER RESPONDS POORLY TO TREATMENT AND IS USUALLY FATAL. HERE, WE DISCUSS WHAT IS KNOWN ABOUT THE MOLECULAR MECHANISMS LEADING TO BLASTIC TRANSFORMATION OF CML AND PROPOSE SOME NOVEL THERAPEUTIC APPROACHES. 2010 11 1685 34 DRUGGABLE BIOCHEMICAL PATHWAYS AND POTENTIAL THERAPEUTIC ALTERNATIVES TO TARGET LEUKEMIC STEM CELLS AND ELIMINATE THE RESIDUAL DISEASE IN CHRONIC MYELOID LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A DISEASE ARISING IN STEM CELLS EXPRESSING THE BCR-ABL ONCOGENIC TYROSINE KINASE THAT TRANSFORMS ONE HEMATOPOIETIC STEM/PROGENITOR CELL INTO A LEUKEMIC STEM CELL (LSC) AT THE ORIGIN OF DIFFERENTIATED AND PROLIFERATING LEUKEMIC CELLS IN THE BONE MARROW (BM). CML-LSCS ARE RECOGNIZED AS BEING RESPONSIBLE FOR RESISTANCES AND RELAPSES THAT OCCUR DESPITE THE ADVENT OF BCR-ABL-TARGETING THERAPIES WITH TYROSINE KINASE INHIBITORS (TKIS). LSCS SHARE A LOT OF FUNCTIONAL PROPERTIES WITH HEMATOPOIETIC STEM CELLS (HSCS) ALTHOUGH SOME PHENOTYPICAL AND FUNCTIONAL DIFFERENCES HAVE BEEN DESCRIBED DURING THE LAST TWO DECADES. SUBVERTED MECHANISMS AFFECTING EPIGENETIC PROCESSES, APOPTOSIS, AUTOPHAGY AND MORE RECENTLY METABOLISM AND IMMUNOLOGY IN THE BONE MARROW MICROENVIRONMENT (BMM) HAVE BEEN REPORTED. THE AIM OF THIS REVIEW IS TO BRING TOGETHER THE MODIFICATIONS AND MOLECULAR MECHANISMS THAT ARE KNOWN TO ACCOUNT FOR TKI RESISTANCE IN PRIMARY CML-LSCS AND TO FOCUS ON THE POTENTIAL SOLUTIONS THAT CAN CIRCUMVENT THESE RESISTANCES, IN PARTICULAR THOSE THAT HAVE BEEN, OR WILL BE TESTED IN CLINICAL TRIALS. 2019 12 6789 40 [CURRENT STATUS OF ATL RESEARCH: EFFORTS FOR PREVENTION AND PRECISION MEDICINE FOR ATL]. THE INTRODUCTION OF NEW AGENTS AND HEMATOPOIETIC STEM CELL TRANSPLANTATION INTO THE TREATMENT OF ATL HAS ACTIVATED ITS CLINICAL RESEARCH. HOWEVER, THE PROGNOSIS OF ATL REMAINS POOR COMPARED WITH THOSE OF OTHER LEUKEMIAS AND LYMPHOMAS. THUS, SEEMINGLY WE HAVE TO RECONSIDER A NEW STRATEGY OF ATL THERAPY BASED ON ITS UNIQUE CHARACTERISTICS. HTLV-1 INFECTION OF T CELLS RESULTS IN CLONAL PROLIFERATION OF INFECTED CELLS THAT ACCUMULATE GENETIC AND EPIGENETIC ABNORMALITIES BEFORE THE ONSET OF ATL. THEREFORE, THE TREATMENT STRATEGY SHOULD INCLUDE THE PREVENTION OF HTLV-1 INFECTION AND ATL DEVELOPMENT IN ADDITION TO PRECISION MEDICINE BASED ON THE STRATIFICATION OF ATL CASES BY BIOMARKERS THAT DISCRIMINATE CLINICAL STAGES OF ATL. I SUMMARIZE HERE THE RECENT PROGRESS IN ATL RESEARCH FOCUSING ON THE BIOMOLECULAR ABNORMALITIES THAT LEAD TO CLONAL EXPANSION AND MALIGNANT TRANSFORMATION OF HTLV-1-INFECTED T CELLS. APPARENTLY, ONE OF THE BASES FOR THE PREVENTION OF ATL IS TO ESTABLISH A DISEASE ENTITY OF "CHRONIC ACTIVE HTLV-1 INFECTION" THAT DEFINES HIGH-RISK CARRIERS FOR ATL DEVELOPMENT AND ENABLES PREVENTIVE INTERVENTION. 2017 13 5212 32 PRESERVATION OF QUIESCENT CHRONIC MYELOGENOUS LEUKEMIA STEM CELLS BY THE BONE MARROW MICROENVIRONMENT. THE MAJORITY OF LEUKEMIA PATIENTS ACHIEVING REMISSION ULTIMATELY RELAPSE. PERSISTENCE OF LEUKEMIA STEM CELLS (LSC) CAPABLE OF REGENERATING LEUKEMIA IS A MAJOR CAUSE OF RELAPSE. THERE IS A PRESSING NEED TO BETTER UNDERSTAND MECHANISMS OF LSC REGULATION AND THEIR RESISTANCE TO THERAPY IN ORDER TO IMPROVE OUTCOMES FOR LEUKEMIA. CHRONIC MYELOGENOUS LEUKEMIA (CML) IS A LETHAL MYELOPROLIFERATIVE DISORDER THAT THAT IS CAUSED BY HEMATOPOIETIC STEM CELL (HSC) TRANSFORMATION BY THE BCR-ABL TYROSINE KINASE. TREATMENT WITH TYROSINE KINASE INHIBITORS (TKI) HAS REVOLUTIONIZED CML TREATMENT, BUT FAILS TO ELIMINATE LSC RESPONSIBLE FOR PROPAGATING AND REGENERATING LEUKEMIA. THEREFORE, PATIENTS REQUIRE CONTINUED TREATMENT TO PREVENT RELAPSE. LEUKEMIC AND NORMAL STEM CELLS SHARE PROPERTIES OF QUIESCENCE AND SELF-RENEWAL, THAT ARE SUPPORTED BY BONE MARROW NICHES. PERSISTENCE OF LSC AFTER TKI TREATMENT IS RELATED TO TYROSINE KINASE INDEPENDENT MECHANISMS WHICH INCLUDE INTRINSIC PROPERTIES OF LSCS DETERMINED BY EPIGENETIC ALTERATIONS, ALTERED TRANSCRIPTIONAL REGULATORY NETWORKS OR MITOCHONDRIAL/METABOLIC CHANGES. IN ADDITION TO CELL INTRINSIC CHANGES, SIGNALS FROM THE BONE MARROW MICROENVIRONMENT (BMM) PLAY A CRITICAL ROLE IN PROTECTING LSC FROM TKI TREATMENT. EACH TYPE OF ALTERATION MAY OFFER POTENTIAL POINTS OF INTERVENTION FOR THERAPEUTIC TARGETING OF LSC. 2018 14 4533 41 MULTIPLE GENE KNOCKDOWN STRATEGIES FOR INVESTIGATING THE PROPERTIES OF HUMAN LEUKEMIA STEM CELLS AND EXPLORING NEW THERAPIES. THE PAST TWO DECADES HAVE WITNESSED SIGNIFICANT STRIDES IN LEUKEMIA THERAPIES THROUGH APPROVAL OF THERAPEUTIC INHIBITORS TARGETING ONCOGENE-DRIVING DYSREGULATED TYROSINE KINASE ACTIVITIES AND KEY EPIGENETIC AND APOPTOSIS REGULATORS. ALTHOUGH THESE DRUGS HAVE BROUGHT ABOUT COMPLETE REMISSION IN THE MAJORITY OF PATIENTS, MANY PATIENTS FACE RELAPSE OR HAVE REFRACTORY DISEASE. THE MAIN FACTOR CONTRIBUTING TO RELAPSE IS THE PRESENCE OF A SMALL SUBPOPULATION OF DORMANT DRUG-RESISTANT LEUKEMIA CELLS THAT POSSESS STEM CELL FEATURES (TERMED AS LEUKEMIA STEM CELLS OR LSCS). THUS, OVERCOMING DRUG RESISTANCE AND TARGETING LSCS REMAIN MAJOR CHALLENGES FOR CURATIVE TREATMENT OF HUMAN LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A GOOD EXAMPLE, WITH RARE, PROPAGATING LSCS AND DRUG-RESISTANT CELLS THAT CANNOT BE ERADICATED BY BCR-ABL-DIRECTED TYROSINE KINASE INHIBITOR (TKI) MONOTHERAPY AND THAT ARE RESPONSIBLE FOR DISEASE RELAPSE/PROGRESSION. THEREFORE, IT IS IMPERATIVE TO IDENTIFY KEY PLAYERS IN REGULATING BCR-ABL1-DEPENDENT AND INDEPENDENT DRUG-RESISTANCE MECHANISMS, AND THEIR KEY PATHWAYS, SO THAT CML LSCS CAN BE SELECTIVELY TARGETED OR SENSITIZED TO TKIS. HERE, WE DESCRIBE SEVERAL EASILY ADAPTABLE GENE KNOCKDOWN APPROACHES IN CD34(+) CML STEM/PROGENITOR CELLS THAT CAN BE USED TO INVESTIGATE THE BIOLOGICAL PROPERTIES OF LSCS AND MOLECULAR EFFECTS OF GENES OF INTEREST (GOI), WHICH CAN BE FURTHER EXPLORED AS THERAPEUTIC MODALITIES AGAINST LSCS IN THE CONTEXT OF HUMAN LEUKEMIA. 2022 15 2538 27 EPIGENETICS IN HEPATOCELLULAR CARCINOMA: AN UPDATE AND FUTURE THERAPY PERSPECTIVES. HEPATOCELLULAR CARCINOMA (HCC), THE PREDOMINANT FORM OF ADULT LIVER MALIGNANCIES, IS A GLOBAL HEALTH CONCERN. ITS DISMAL PROGNOSIS HAS PROMPTED RECENT SIGNIFICANT ADVANCES IN THE UNDERSTANDING OF ITS ETIOLOGY AND PATHOGENESIS. THE DEREGULATION OF EPIGENETIC MECHANISMS, WHICH MAINTAIN HERITABLE GENE EXPRESSION CHANGES AND CHROMATIN ORGANIZATION, IS IMPLICATED IN THE DEVELOPMENT OF MULTIPLE CANCERS, INCLUDING HCC. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE OF EPIGENETIC MECHANISMS IN THE PATHOGENESIS OF HCC, WITH AN EMPHASIS ON HCC MEDIATED BY CHRONIC HEPATITIS B VIRUS INFECTION. THIS REVIEW ALSO DISCUSSES THE ENCOURAGING OUTCOMES AND LESSONS LEARNT FROM EPIGENETIC THERAPIES FOR HEMATOLOGICAL AND OTHER SOLID CANCERS, AND HIGHLIGHTS THE FUTURE POTENTIAL OF SIMILAR THERAPIES IN THE TREATMENT OF HCC. 2014 16 2277 29 EPIGENETIC REGULATION BY ASXL1 IN MYELOID MALIGNANCIES. MYELOID MALIGNANCIES ARE CLONAL HEMATOPOIETIC DISORDERS THAT ARE COMPRISED OF A SPECTRUM OF GENETICALLY HETEROGENEOUS DISORDERS, INCLUDING MYELODYSPLASTIC SYNDROMES (MDS), MYELOPROLIFERATIVE NEOPLASMS (MPN), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), AND ACUTE MYELOID LEUKEMIA (AML). MYELOID MALIGNANCIES ARE CHARACTERIZED BY EXCESSIVE PROLIFERATION, ABNORMAL SELF-RENEWAL, AND/OR DIFFERENTIATION DEFECTS OF HEMATOPOIETIC STEM CELLS (HSCS) AND MYELOID PROGENITOR CELLS HEMATOPOIETIC STEM/PROGENITOR CELLS (HSPCS). MYELOID MALIGNANCIES CAN BE CAUSED BY GENETIC AND EPIGENETIC ALTERATIONS THAT PROVOKE KEY CELLULAR FUNCTIONS, SUCH AS SELF-RENEWAL, PROLIFERATION, BIASED LINEAGE COMMITMENT, AND DIFFERENTIATION. ADVANCES IN NEXT-GENERATION SEQUENCING LED TO THE IDENTIFICATION OF MULTIPLE MUTATIONS IN MYELOID NEOPLASMS, AND MANY NEW GENE MUTATIONS WERE IDENTIFIED AS KEY FACTORS IN DRIVING THE PATHOGENESIS OF MYELOID MALIGNANCIES. THE POLYCOMB PROTEIN ASXL1 WAS IDENTIFIED TO BE FREQUENTLY MUTATED IN ALL FORMS OF MYELOID MALIGNANCIES, WITH MUTATIONAL FREQUENCIES OF 20%, 43%, 10%, AND 20% IN MDS, CMML, MPN, AND AML, RESPECTIVELY. SIGNIFICANTLY, ASXL1 MUTATIONS ARE ASSOCIATED WITH A POOR PROGNOSIS IN ALL FORMS OF MYELOID MALIGNANCIES. THE FACT THAT ASXL1 MUTATIONS ARE ASSOCIATED WITH POOR PROGNOSIS IN PATIENTS WITH CMML, MDS, AND AML, POINTS TO THE POSSIBILITY THAT ASXL1 MUTATION IS A KEY FACTOR IN THE DEVELOPMENT OF MYELOID MALIGNANCIES. THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN UNDERSTANDING MYELOID MALIGNANCIES WITH A SPECIFIC FOCUS ON ASXL1 MUTATIONS. 2023 17 442 28 ANTIVIRAL THERAPIES FOR HEPATITIS B VIRUS-RELATED HEPATOCELLULAR CARCINOMA. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS A CRITICAL RISK FACTOR FOR THE CARCINOGENESIS AND PROGRESSION OF HEPATOCELLULAR CARCINOMA (HCC). IT PROMOTES HCC DEVELOPMENT BY INDUCING LIVER FIBROGENESIS, GENETIC AND EPIGENETIC ALTERATIONS, AND THE EXPRESSION OF ACTIVE VIRAL-CODED PROTEINS. EFFECTIVE ANTIVIRAL TREATMENTS INHIBIT THE REPLICATION OF HBV, REDUCE SERUM VIRAL LOAD AND ACCELERATE HEPATITIS B E ANTIGEN SERUM CONVERSION. TIMELY INITIATION OF ANTIVIRAL TREATMENT IS NOT ONLY ESSENTIAL FOR PREVENTING THE INCIDENCE OF HCC IN CHRONIC HEPATITIS B PATIENTS, BUT ALSO IMPORTANT FOR REDUCING HBV REACTIVATION, IMPROVING LIVER FUNCTION, REDUCING OR DELAYING HCC RECURRENCE, AND PROLONGING OVERALL SURVIVAL OF HBV-RELATED HCC PATIENTS AFTER CURATIVE AND PALLIATIVE THERAPIES. THE SELECTION OF ANTIVIRAL DRUGS, MONITORING OF INDICATORS SUCH AS HBV DNA AND HEPATITIS B SURFACE ANTIGEN, AND TIMELY RESCUE TREATMENT WHEN NECESSARY, ARE ESSENTIAL IN ANTIVIRAL THERAPIES FOR HBV-RELATED HCC. 2015 18 6609 34 TYROSINE KINASE INHIBITORS IN PH+ CHRONIC MYELOID LEUKEMIA THERAPY: A REVIEW. CHRONIC MYELOID LEUKAEMIA (CML) IS A CLONAL MYELOPROLIFERATIVE HEMATOPOIETIC STEM CELL DISORDER. DEREGULATED BCRABL FUSION TYROSINE KINASE ACTIVITY IS THE MAIN CAUSE OF CML DISEASE PATHOGENESIS, MAKING BCRABL AN IDEAL TARGET FOR INHIBITION. CURRENT TYROSINE KINASE INHIBITORS (TKIS) DESIGNED TO INHIBIT BCRABL ONCOPROTEIN ACTIVITY, HAVE COMPLETELY TRANSFORMED THE PROGNOSIS OF CML. INTERRUPTION OF TKI TREATMENT LEADS TO MINIMAL RESIDUAL DISEASE RESIDE (MRD), THOUGHT TO RESIDE IN TKIINSENSITIVE LEUKAEMIA STEM CELLS WHICH REMAIN A POTENTIAL RESERVOIR FOR DISEASE RELAPSE. THIS HIGHLIGHTS THE NEED TO DEVELOP NEW THERAPEUTIC STRATEGIES FOR CML EITHER AS SMALL MOLECULE MASTER TKIS OR PHYTOPHARMACEUTICALS DERIVED FROM NATURE TO ACHIEVE CHRONIC MOLECULAR REMISSION. THIS REVIEW OUTLINES THE PAST, PRESENT AND FUTURE THERAPEUTIC APPROACHES FOR CML INCLUDING COVERAGE OF RELEVANT MECHANISMS, WHETHER ABL DEPENDENT OR INDEPENDENT, AND EPIGENETIC FACTORS RESPONSIBLE FOR DEVELOPING RESISTANCE AGAINST TKIS. APPEARANCE OF MUTANT CLONES ALONG THE COURSE OF THERAPY EITHER PREEXISTING OR INDUCED DUE TO THERAPY IS STILL A CHALLENGE FOR THE CLINICIAN. A PROPOSED INVITRO MODEL OF GENERATING COLONY FORMING UNITS FROM CML STEM CELLS DERIVED FROM DIAGNOSTIC SAMPLES SEEMS TO BE ACHIEVABLE IN THE ERA OF HIGH THROUGHPUT TECHNOLOGY WHICH CAN TAKE CARE OF SINGLE CELL GENOMIC PROFILING. 2016 19 4436 27 MOLECULAR EVOLUTION OF CHRONIC MYELOID LEUKAEMIA. CHRONIC MYELOID LEUKAEMIA (CML) IS A CLONAL DISORDER OF THE PLURIPOTENT HAEMATOPOIETIC STEM CELL. THE TYPICAL TRIPHASIC COURSE OF CML STARTS WITH THE PREMALIGNANT CHRONIC PHASE INITIATED BY BCR-ABL HYBRID ONCOGENE FORMATION. SECONDARY GENETIC AND EPIGENETIC ABERRATIONS ACCOMPANY THE PROGRESSION TO THE ACCELERATED PHASE AND FATAL BLASTIC CRISIS. PROPERLY TIMED BONE MARROW TRANSPLANTATION IN ELIGIBLE PATIENTS CAN RESULT IN DURABLE REMISSIONS OR CURE. BOTH OF THESE STATES ARE OFTEN ACCOMPANIED BY A LONG-TERM PERSISTENCE OF QUIESCENT LEUKAEMIC CELLS. ACCORDINGLY, A "FUNCTIONAL CURE" (I.E. TUMOUR DORMANCY INDUCTION), RATHER THAN COMPLETE ERADICATION OF THE MALIGNANT CELLS, IS AN ADEQUATE THERAPEUTICAL GOAL. THE LEVEL OF THE RESIDUAL BCR-ABL-POSITIVE CLONES SHOULD BE MONITORED AND SALVAGE TREATMENT INITIATED WHENEVER THESE QUIESCENT LEUKAEMIC CELLS EXIT THEIR DORMANT STATE. 2001 20 1940 22 EPIDEMIOLOGY AND CARCINOGENESIS OF HEPATOCELLULAR CARCINOMA. THE INCIDENCE OF HEPATOCELLULAR CARCINOMA (HCC) SHOWS MARKED VARIATION WORLDWIDE BUT THE MAGNITUDE OF THIS TUMOR IS REFLECTED BY THE OCCURRENCE OF AT LEAST 1 MILLION NEW CASES ANNUALLY AND THE UNIFORMLY DISMAL OUTLOOK WITH MEDIAN SURVIVALS OF <25 MONTHS AFTER RESECTION AND <6 MONTHS WITH SYMPTOMATIC TREATMENT. THE STRIKINGLY UNEVEN DISTRIBUTION OF THIS TUMOR PARALLELS THE PREVALENCE OF HEPATITIS B INFECTION WITH RISING INCIDENCE IN WESTERN COUNTRIES ATTRIBUTED TO HEPATITIS C INFECTION. CHRONIC HEPATITIS AND CIRRHOSIS CONSTITUTE THE MAJOR PRENEOPLASTIC CONDITIONS IN THE MAJORITY OF HCCS AND MAY BE RELATED TO OTHER ETIOLOGIC AGENTS SUCH AS ENVIRONMENTAL CHEMICAL CARCINOGENS INCLUDING NITRITES, HYDROCARBONS, SOLVENTS, ORGANOCHLORINE PESTICIDES, AND THE CHEMICALS IN PROCESSED FOODS, CLEANING AGENTS, COSMETICS AND PHARMACEUTICALS, AS WELL AS PLANT TOXINS SUCH AS ANATOXINS PRODUCED BY FUNGI THAT CAUSE SPOILAGE OF GRAIN AND FOOD IN THE TROPICS. GENETIC DISEASES SUCH AS GENETIC HEMATOCHROMATOSIS, WILSON'S DISEASE, ALPHA-1-ANTITRYPSIN DEFICIENCY, AND THE INBORN ERRORS OF METABOLISM INCLUDING HEREDITARY TYROSINEMIA AND HEPATIC PORPHYRIA, ARE KNOWN TO BE ASSOCIATED WITH HCC. NUMEROUS GENETIC ALTERATIONS AND THE MODULATION OF DNA METHYLATION ARE RECOGNIZED IN HCC AND IT IS LIKELY THAT THESE GENETIC AND EPIGENETIC CHANGES COMBINE WITH FACTORS INVOLVED IN CHRONIC HEPATOCYTE DESTRUCTION AND REGENERATION TO RESULT IN NEOPLASTIC GROWTH AND MULTIPLE MOLECULAR PATHWAYS MAY BE INVOLVED IN THE PRODUCTION OF SUBSETS OF HEPATOCELLULAR TUMORS. 2005