Hematopoietic Stem/Progenitor cells (HSPCs) are endowed with the role of maintaining a diverse pool of blood cells throughout the human life. Despite recent efforts, the nature of the early cell fate ...decisions remains contentious. Using single-cell RNA-Seq, we show that existing approaches to stratify bone marrow CD34+ cells reveal a hierarchically-structured transcriptional landscape of hematopoietic differentiation. Still, this landscape misses important early fate decisions. We here provide a broader transcriptional profiling of bone marrow lineage negative hematopoietic progenitors that recovers a key missing branchpoint into basophils and expands our understanding of the underlying structure of early adult human haematopoiesis. We also show that this map has strong similarities in topology and gene expression to that found in mouse. Finally, we identify the sialomucin CD164, as a reliable marker for the earliest branches of HSPCs specification and we showed how its use can foster the design of alternative transplantation cell products.
How I investigate acute myeloid leukemia Narayanan, Damodaran; Weinberg, Olga K.
International journal of laboratory hematology,
February 2020, 2020-Feb, 2020-02-00, 20200201, Letnik:
42, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Acute myeloid leukemia (AML) is a neoplasm of immature myeloid cells and is associated with a wide variety of clinical presentations, morphological features, immunophenotypes, and genetic findings. ...Recent advances in identification of cytogenetic abnormalities and mutations have provided novel insights into the pathogenesis of AML. Based on the above‐mentioned parameters, the World Health Organization (WHO) classified AML into 25 subtypes, including 2 provisional entities, which differ in prognosis and treatment. In addition, certain mutations are associated with germline predisposition and increase the risk of inherited AML, which warrants family screening. Therefore, precise diagnosis and classification of AML are the most important steps in patient management. Both these steps require incorporation of history, clinical presentation, and laboratory results with studies performed by a pathologist. Pathologist‐initiated studies include morphologic evaluation on the bone marrow aspirate and/or core biopsy, immunophenotyping by flow cytometry and/or immunohistochemistry, cytogenetic analysis by karyotyping and/or fluorescence in situ hybridization, and molecular testing using gene panels and/or next‐generation sequencing. A similar approach is employed during follow‐up of patients after beginning treatment. Here, we describe in detail the various aspects of the workup, including purpose, limitations, and practice guidelines for the different studies. The process of choosing appropriate materials for the different studies is also addressed. We also provide an algorithm for the workup and risk stratification of AML based on guidelines recommended by the WHO, College of American Pathologists, National Comprehensive Cancer Network, American Society of Clinical Oncology, European Society of Medical Oncology, and the European LeukemiaNet.
T/myeloid mixed phenotype acute leukaemia (MPAL) is a rare aggressive acute leukaemia with poorly understood pathogenesis. Herein, we report two cases of T/myeloid MPAL harbouring BCL11B-associated ...structural variants that activate TLX3 (TLX3::BCL11B-TLX3-activation) by genome sequencing and transcriptomic analyses. Both patients were young males with extramedullary involvement. Cooperative gene alterations characteristic of T/myeloid MPAL and T-lymphoblastic leukaemia (T-ALL) were detected. Both patients achieved initial remission following lineage-matched ALL-based therapy with one patient requiring a lineage-switched myeloid-based therapy. Our study is the first to demonstrate the clinicopathological and genomic features of TLX3::BCL11B-TLX3-activated T/myeloid MPAL and provide insights into leukaemogenesis.
Unexplained blood cytopenias, in particular anemia, are often found in older individuals. The relationship between these cytopenias and myeloid neoplasms like myelodysplastic syndromes is currently ...poorly defined. Terminology used to describe patients with unexplained cytopenias and with clonally restricted hematopoiesis can be confusing and is evolving. This review uses a complex clinical case with borderline morphology and somatic mutations with high variant allele frequencies to illustrate a diagnostic approach to clonal cytopenias, and differentiation from myeloid neoplasms with a focus on appropriate ancillary testing. Testing for somatic mutations and variant allele frequency is helpful in assessing risk for progression to myeloid malignancy. The interpretation of mutation profiles in patients with cytopenia has been challenging, as some of these genes are commonly detected in elderly adults showing a normal blood count as well as in individuals with nonmalignant bone marrow failure syndromes. For patients with unexplained cytopenias, longitudinal follow‐up including monitoring of blood counts may also be appropriate.
Abstract
The blast phase of
BCR::ABL1
‐negative myeloproliferative neoplasm (MPN‐BP) represents the final stage of the disease, which is complicated by complex genomic alterations. These alterations ...result from sequence changes in genetic material (DNA, RNA) and can lead to either a gain or loss of function of encoded proteins, such as adaptor proteins, enzymes, components of spliceosomes, cell cycle checkpoints regulators, transcription factors, or proteins in cell signaling pathways. Interference at various levels, including transcription, translation, and post‐translational modification (such as methylation, dephosphorylation, or acetylation), can contribute to these alterations. Mutated genes such as
ASXL1, EZH2, IDH1, IDH2, TET2, SRSF2, U2AF1, TP53, NRAS, KRAS, PTPN11, SH2B3/LNK
, and
RUNX1
play active roles at different stages of genetic material expression, modification, and protein function manipulation in MPNs. These mutations are also correlated with, and can contribute to, the progression of MPN‐BP. In this review, we summarize their common mutational profiles, functions, and associations with progression of MPN‐BP.
Next generation sequencing has uncovered several genes with associated mutations in hematologic malignancies that can serve as potential biomarkers of disease. Keeping abreast of these genes is ...therefore of paramount importance in the field of hematology. This review focuses on
PHF6
, a highly conserved epigenetic transcriptional regulator that is important for neurodevelopment and hematopoiesis.
PHF
6 serves as a tumor suppressor protein, with
PHF6
mutations and deletions often implicated in the development of T-lymphoblastic leukemia and less frequently in acute myeloid leukemia and other myeloid neoplasms.
PHF6
inactivation appears to be an early event in T-lymphoblastic leukemogenesis, requiring cooperating events, including
NOTCH1
mutations or overexpression of TLX1 and TLX3 for full disease development. In contrast,
PHF6
mutations tend to occur later in myeloid malignancies, are frequently accompanied by
RUNX1
mutations, and are often associated with disease progression. Moreover,
PHF
6 appears to play a role in lineage plasticity within hematopoietic malignancies, with
PHF6
mutations commonly present in mixed phenotype acute leukemias with a predilection for T-lineage marker expression. Due to conflicting data, the prognostic significance of
PHF6
mutations remains unclear, with a subset of studies showing no significant difference in outcomes compared to malignancies with wild-type
PHF6
, and other studies showing inferior outcomes in certain patients with mutated
PHF6.
Future studies are necessary to elucidate the role
PHF6
plays in development of T-lymphoblastic leukemia, progression of myeloid malignancies, and its overall prognostic significance in hematopoietic neoplasms.
Abstract
Objectives
Classification of acute leukemia involves assigning lineage by resemblance to normal progenitor cells. This approach provides descriptive information about the blast cells that is ...useful for disease monitoring, provides clues to pathogenesis, and can help clinicians select effective chemotherapeutic regimens. Acute leukemias of ambiguous lineage (ALALs) are those leukemias that either fail to show evidence of myeloid, B-, or T-lymphoid lineage commitment or show evidence of commitment to more than 1 lineage. The different treatment regimens for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) make ALAL a challenge both diagnostically and therapeutically.
Methods
Current classification criteria have reduced the reported incidence of mixed-lineage leukemias by emphasizing fewer markers and categorizing some biphenotypic leukemias with recurrent cytogenetic abnormalities as other entities. Several recent studies have explored the genomic and epigenetic landscape of mixed-phenotype acute leukemia (MPAL) and have suggested a further refinement of the World Health Organization classification to emphasize the genomic heterogeneity of MPAL.
Results
Genomic and expression profile data for MPAL reveal mutations commonly seen in both AML and ALL, with T-/myeloid MPAL showing overlapping features with early T-cell precursor lymphoblastic leukemia.
Conclusions
Our review aimed to discuss the diagnostic challenges, recent genomic studies, and therapeutic strategies in this poorly understood disease.
Objectives: The 2017 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review clinical cases with germline predisposition to hematolymphoid neoplasms. ...Methods: The Workshop Panel reviewed 51 cases with germline mutations and rendered consensus diagnoses. Of these, six cases were presented at the meeting by the submitting pathologists. Results: The cases submitted to the session covering germline predisposition included 16 cases with germline GATA2 mutations, 10 cases with germline RUNX1 mutations, two cases with germline CEBPA mutations, two germline TP53 mutations, and one case of germline DDX41 mutation. The most common diagnoses were acute myeloid leukemia (15 cases) and myelodysplastic syndrome (MDS, 14 cases). Conclusions: The majority of the submitted neoplasms occurring in patients with germline predisposition were myeloid neoplasms with germline mutations in GATA2 and RUNX1. The presence of a germline predisposition mutation is not sufficient for a diagnosis of a neoplasm until the appearance of standard diagnostic features of a hematolymphoid malignancy manifest: in general, the diagnostic criteria for neoplasms associated with germline predisposition disorders are the same as those for sporadic cases. Key Words: Germline predisposition; GATA2; RUNX1; CEBPA; Molecular genetics; Targeted therapy; Hematolymphoid neoplasia; MDS; AML
The 2017 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review clinical cases with germline predisposition to hematolymphoid neoplasms.
The Workshop ...Panel reviewed 51 cases with germline mutations and rendered consensus diagnoses. Of these, six cases were presented at the meeting by the submitting pathologists.
The cases submitted to the session covering germline predisposition included 16 cases with germline GATA2 mutations, 10 cases with germline RUNX1 mutations, two cases with germline CEBPA mutations, two germline TP53 mutations, and one case of germline DDX41 mutation. The most common diagnoses were acute myeloid leukemia (15 cases) and myelodysplastic syndrome (MDS, 14 cases).
The majority of the submitted neoplasms occurring in patients with germline predisposition were myeloid neoplasms with germline mutations in GATA2 and RUNX1. The presence of a germline predisposition mutation is not sufficient for a diagnosis of a neoplasm until the appearance of standard diagnostic features of a hematolymphoid malignancy manifest: in general, the diagnostic criteria for neoplasms associated with germline predisposition disorders are the same as those for sporadic cases.
PDF
