-
Oncogene Mar 2016HOXA9 is a homeodomain-containing transcription factor that has an important role in hematopoietic stem cell expansion and is commonly deregulated in acute leukemias. A... (Review)
Review
HOXA9 is a homeodomain-containing transcription factor that has an important role in hematopoietic stem cell expansion and is commonly deregulated in acute leukemias. A variety of upstream genetic alterations in acute myeloid leukemia lead to overexpression of HOXA9, which is a strong predictor of poor prognosis. In many cases, HOXA9 has been shown to be necessary for maintaining leukemic transformation; however, the molecular mechanisms through which it promotes leukemogenesis remain elusive. Recent work has established that HOXA9 regulates downstream gene expression through binding at promoter distal enhancers along with a subset of cell-specific cofactor and collaborator proteins. Increasing efforts are being made to identify both the critical cofactors and target genes required for maintaining transformation in HOXA9-overexpressing leukemias. With continued advances in understanding HOXA9-mediated transformation, there is a wealth of opportunity for developing novel therapeutics that would be applicable for greater than 50% of AML with overexpression of HOXA9.
Topics: Carcinogenesis; Gene Expression Regulation, Leukemic; Homeodomain Proteins; Humans; Leukemia; Molecular Targeted Therapy; Promoter Regions, Genetic
PubMed: 26028034
DOI: 10.1038/onc.2015.174 -
International Journal of Molecular... Apr 2022Refractory disease and relapse remain the main causes of cancer therapy failure. Refined risk stratification, treatment regimens and improved early diagnosis and... (Review)
Review
Refractory disease and relapse remain the main causes of cancer therapy failure. Refined risk stratification, treatment regimens and improved early diagnosis and detection of minimal residual disease have increased cure rates in malignancies like childhood acute lymphoblastic leukaemia (ALL) to 90%. Nevertheless, overall survival in the context of drug resistance remains poor. The regulatory role of micro RNAs (miRNAs) in cell differentiation, homeostasis and tumorigenesis has been under extensive investigation in different cancers. There is accumulating data demonstrating the significance of miRNAs for therapy outcomes in lymphoid malignancies and some direct demonstrations of the interplay between these small molecules and drug response. Here, we summarise miRNAs' impact on chemotherapy resistance in adult and paediatric ALL and chronic lymphocytic leukaemia (CLL). The main focus of this review is on the modulation of particular signaling pathways like PI3K-AKT, transcription factors such as NF-κB, and apoptotic mediators, all of which are bona fide and pivotal elements orchestrating the survival of malignant lymphocytic cells. Finally, we discuss the attractive strategy of using mimics, antimiRs and other molecular approaches pointing at miRNAs as promising therapeutic targets. Such novel strategies to circumvent ALL and CLL resistance networks may potentially improve patients' responses and survival rates.
Topics: Adult; Child; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; MicroRNAs; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Signal Transduction
PubMed: 35563051
DOI: 10.3390/ijms23094657 -
International Journal of Molecular... Aug 2018Blood formation, or haematopoiesis, originates from haematopoietic stem cells (HSCs), whose functions and maintenance are regulated in both cell- and cell non-autonomous... (Review)
Review
Blood formation, or haematopoiesis, originates from haematopoietic stem cells (HSCs), whose functions and maintenance are regulated in both cell- and cell non-autonomous ways. The surroundings of HSCs in the bone marrow create a specific niche or microenvironment where HSCs nest that allows them to retain their unique characteristics and respond rapidly to external stimuli. Ageing is accompanied by reduced regenerative capacity of the organism affecting all systems, due to the progressive decline of stem cell functions. This includes blood and HSCs, which contributes to age-related haematological disorders, anaemia, and immunosenescence, among others. Furthermore, chronological ageing is characterised by myeloid and platelet HSC skewing, inflammageing, and expanded clonal haematopoiesis, which may be the result of the accumulation of preleukaemic lesions in HSCs. Intriguingly, haematological malignancies such as acute myeloid leukaemia have a high incidence among elderly patients, yet not all individuals with clonal haematopoiesis develop leukaemias. Here, we discuss recent work on these aspects, their potential underlying molecular mechanisms, and the first cues linking age-related changes in the HSC niche to poor HSC maintenance. Future work is needed for a better understanding of haematopoiesis during ageing. This field may open new avenues for HSC rejuvenation and therapeutic strategies in the elderly.
Topics: Aging; Animals; Bone Marrow; Hematopoiesis; Humans; Leukemia
PubMed: 30158459
DOI: 10.3390/ijms19092567 -
Revue Medicale de Liege May 2021Acute leukemias are a heterogeneous group of malignant hemopathies which are subdivided according to the cytological orientation of the pathological blast cell into... (Review)
Review
Acute leukemias are a heterogeneous group of malignant hemopathies which are subdivided according to the cytological orientation of the pathological blast cell into lymphoblastic (ALL) and myeloblastic (AML) acute leukemias. Recent advances in the biological and genetic understanding of these diseases have led to improved treatments. Specific chemotherapy treatment or so-called «targeted» treatments, advances in bone marrow transplantation and better supportive care have gradually improved the prognosis. This review, focused on the adult patient, aims to describe recent progress in terms of diagnosis, prognostic markers and therapy.
Topics: Acute Disease; Adult; Bone Marrow Transplantation; Humans; Leukemia, Myeloid, Acute; Prognosis
PubMed: 34080382
DOI: No ID Found -
The Oncologist 1999Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in infants have in common a high incidence of translocations of the MLL gene at chromosome band... (Review)
Review
Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in infants have in common a high incidence of translocations of the MLL gene at chromosome band 11q23. Similar translocations occur in leukemias associated with chemotherapies that target DNA topoisomerase II. MLL has numerous different partner genes. The role of the many MLL fusion proteins in leukemogenesis is not yet understood. The t(4;11) translocation, the most common translocation in infant ALL, adversely affects the outcome. Additional genetic changes, especially Ikaros alterations, are found in infant ALL. Other forms of myeloid leukemia in infants present as myelodysplastic and myeloproliferative syndromes, which may be associated with constitutional disorders. This review will consider all leukemia in infants, but will focus on leukemias with MLL gene translocations.
Topics: Antineoplastic Agents; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 4; Female; Humans; Incidence; Infant; Infant, Newborn; Leukemia, Myelomonocytic, Acute; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Translocation, Genetic
PubMed: 10394590
DOI: No ID Found -
Journal of Ayub Medical College,... 2022Acute Leukaemia is a malignant disorder characterized by an abnormal proliferation of immature cells, called blasts. Classically, acute leukaemia is classified into...
BACKGROUND
Acute Leukaemia is a malignant disorder characterized by an abnormal proliferation of immature cells, called blasts. Classically, acute leukaemia is classified into acute myeloid leukaemia and acute lymphoblastic leukaemia depending on the lineage of the immature cells. Objective of the study was to evaluate the clinical presentations, analyze the haematologic parameters at time of diagnosis and assess the post-induction status in newly diagnosed ALL patients. This cross-sectional study was conducted in the Department of Haematology, Armed Forces Institute of Pathology, Rawalpindi from June to November 2019.
METHODS
A total of 55 newly diagnosed ALL patients were recruited including children, adults and elderly. Detailed medical history and physical findings were noted. Haematologic parameters were documented. Each patient was treated as per standard protocol and remission induction status was determined on day 29 of treatment.
RESULTS
The median age of the study cohort of 55 newly diagnosed ALL patients was 8.5 years. Males were 37 (67.3%) and females were 18 (32.7%) with a male to female ratio of 2:1. Paediatric group included 31 (56.4%) patients. Nine (16.4%) patients were in the adult group and 15 (27.3%) in the elderly age group. The time from onset of symptoms to diagnosis of acute lymphoblastic leukaemia was 98.87±79.21 days. Fever was the most common symptom but body aches were common among paediatric group while pallor was the most common sign. Mean WBC was 29.1±27.9 x109/l, Hb was 8.1±2.9 g/dl and platelet count was 60±41.8 x109/l B-acute lymphoblastic leukaemia was more common than T-acute lymphoblastic leukaemia. A total of 52 patients were assessed on day 29 to evaluate for post-induction remission status. The remission rate of our cohort of patients was 82.7%.
CONCLUSIONS
Most of the patients were in paediatric age group and remission rate was better in this age group compared to elderly population. B-ALL was associated with good response to induction chemotherapy while patients with BCR-ABL1 gene rearrangement did not respond well to treatment. Identification of prognostic features at diagnosis will further help our clinicians to predict outcomes of the disease.
Topics: Humans; Aged; Child; Adult; Male; Female; Cross-Sectional Studies; Antineoplastic Combined Chemotherapy Protocols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Leukemia, Myeloid, Acute; Hematology
PubMed: 36377156
DOI: 10.55519/JAMC-03-10448 -
Archives of Pathology & Laboratory... Mar 2008The diagnosis and classification of leukemia is becoming increasingly complex. Current classification schemes incorporate morphologic features, immunophenotype,... (Review)
Review
CONTEXT
The diagnosis and classification of leukemia is becoming increasingly complex. Current classification schemes incorporate morphologic features, immunophenotype, molecular genetics, and clinical data to specifically categorize leukemias into various subtypes. Although sophisticated methodologies are frequently used to detect characteristic features conferring diagnostic, prognostic, or therapeutic implications, a thorough microscopic examination remains essential to the pathologic evaluation. Detailed blast immunophenotyping can be performed with lineage- and maturation-specific markers. Although no one marker is pathognomonic for one malignancy, a well-chosen panel of antibodies can efficiently aid the diagnosis and classification of acute leukemias.
OBJECTIVE
To review important developments from recent and historical literature. General immunohistochemical staining patterns of the most commonly encountered lymphoid and myeloid leukemias are emphasized. The goal is to discuss the immunostaining of acute leukemias when flow cytometry and genetic studies are not available.
DATA SOURCES
A comprehensive review was performed of the relevant literature indexed in PubMed (National Library of Medicine) and referenced medical texts. Additional references were identified in the reviewed manuscripts.
CONCLUSIONS
Immunophenotyping of blasts using an immunohistochemical approach to lymphoid and myeloid malignancies is presented. Initial and subsequent additional antibody panels are suggested to confirm or exclude each possibility in the differential diagnosis and a general strategy for diagnostic evaluation is discussed. Although the use of immunohistochemistry alone is limited and evaluation by flow cytometry and genetic studies is highly recommended, unavoidable situations requiring analysis of formalin-fixed tissue specimens arise. When performed in an optimized laboratory and combined with a careful morphologic examination, the immunohistochemical approach represents a useful laboratory tool for classifying various leukemias.
Topics: Acute Disease; Biomarkers, Tumor; Flow Cytometry; Humans; Immunohistochemistry; Leukemia
PubMed: 18318587
DOI: 10.5858/2008-132-462-ALIASD -
International Journal of Molecular... Nov 2017The most common acute hematological malignancy in adults is acute myeloid leukaemia (AML), accounting for more than 80% of cases in patients over 60 years of age [...].
The most common acute hematological malignancy in adults is acute myeloid leukaemia (AML), accounting for more than 80% of cases in patients over 60 years of age [...].
Topics: Adult; Female; Humans; Leukemia, Myeloid, Acute; Male
PubMed: 29189736
DOI: 10.3390/ijms18122577 -
Hematological Oncology Oct 2020The meeting, which brought together leading scientists and clinicians in the field of leukemia and lymphoma, was held at the new headquarters of the Josep Carreras... (Review)
Review
The meeting, which brought together leading scientists and clinicians in the field of leukemia and lymphoma, was held at the new headquarters of the Josep Carreras Leukaemia Research Institute (IJC) in Badalona, Catalonia, Spain, September 19-20, 2019. Its purpose was to highlight the latest advances in our understanding of the molecular mechanisms driving blood cancers, and to discuss how this knowledge can be translated into an improved management of the disease. Special emphasis was placed on the role of genetic and epigenetic heterogeneity, and the exploitation of epigenetic regulation for developing biomarkers and novel treatment approaches.
Topics: Congresses as Topic; DNA Methylation; Epigenesis, Genetic; Genomics; Humans; Leukemia; Lymphoma
PubMed: 32073154
DOI: 10.1002/hon.2725 -
Haematologica Sep 2016To characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesions, we analyzed 44 new and published...
To characterize the incidence, clinical features and genetics of ETV6-ABL1 leukemias, representing targetable kinase-activating lesions, we analyzed 44 new and published cases of ETV6-ABL1-positive hematologic malignancies [22 cases of acute lymphoblastic leukemia (13 children, 9 adults) and 22 myeloid malignancies (18 myeloproliferative neoplasms, 4 acute myeloid leukemias)]. The presence of the ETV6-ABL1 fusion was ascertained by cytogenetics, fluorescence in-situ hybridization, reverse transcriptase-polymerase chain reaction and RNA sequencing. Genomic and gene expression profiling was performed by single nucleotide polymorphism and expression arrays. Systematic screening of more than 4,500 cases revealed that in acute lymphoblastic leukemia ETV6-ABL1 is rare in childhood (0.17% cases) and slightly more common in adults (0.38%). There is no systematic screening of myeloproliferative neoplasms; however, the number of ETV6-ABL1-positive cases and the relative incidence of acute lymphoblastic leukemia and myeloproliferative neoplasms suggest that in adulthood ETV6-ABL1 is more common in BCR-ABL1-negative chronic myeloid leukemia-like myeloproliferations than in acute lymphoblastic leukemia. The genomic profile of ETV6-ABL1 acute lymphoblastic leukemia resembled that of BCR-ABL1 and BCR-ABL1-like cases with 80% of patients having concurrent CDKN2A/B and IKZF1 deletions. In the gene expression profiling all the ETV6-ABL1-positive samples clustered in close vicinity to BCR-ABL1 cases. All but one of the cases of ETV6-ABL1 acute lymphoblastic leukemia were classified as BCR-ABL1-like by a standardized assay. Over 60% of patients died, irrespectively of the disease or age subgroup examined. In conclusion, ETV6-ABL1 fusion occurs in both lymphoid and myeloid leukemias; the genomic profile and clinical behavior resemble BCR-ABL1-positive malignancies, including the unfavorable prognosis, particularly of acute leukemias. The poor outcome suggests that treatment with tyrosine kinase inhibitors should be considered for patients with this fusion.
Topics: Adolescent; Adult; Aged; Alternative Splicing; Child; Child, Preschool; Cluster Analysis; DNA Copy Number Variations; Female; Gene Expression Profiling; Humans; In Situ Hybridization, Fluorescence; Infant; Leukemia; Male; Middle Aged; Oncogene Proteins, Fusion; Phenotype; Polymorphism, Single Nucleotide; Protein-Tyrosine Kinases; Transcriptome; Translocation, Genetic; Young Adult
PubMed: 27229714
DOI: 10.3324/haematol.2016.144345