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Familial Acute Myeloid Leukemia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The molecular genetic aberration underlying familial platelet disorders with propensity to myeloid malignancies [online Mendelian inheritance in man (OMIM) #601399] including acute myeloid leukemia (FPD/AML) was identified in 1999 as germline mutations in the RUNX1 gene [6], located in chromosome 21q22.12 band at the breakpoint in the t(8;21) translocation, the source from where RUNXI was originally cloned [28]. RUNX1, previously known as AML1, is critical for embryogenesis and hematopoiesis [29]. For the latter functions, RUNX1 encodes for a protein that complexes with core binding factor β to form a heterodimeric core binding factor complex that regulates the expression of several genes critical for hematopoiesis [30]. In FPD/AML, mutations located in the highly conserved runt homology domain of the RUNX1 gene cause a loss of RUNX1 function and are associated with a high incidence of hematologic myeloid malignancies including myelodysplasia and acute myeloid leukemia [31], and with a lower incidence of lymphoid malignancies including acute lymphoblastic leukemia and hairy cell leukemia [32,33]. At least 40 different mutations have been identified thus far in individuals with FPD/AML, with the majority being missense, and including nonsense, insertions, deletions, or splice site mutations [34].
Immunologic and functional differences among individual compartments of the mucosal immune system
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Hiroshi Kiyono, Kohtaro Fujihashi, Jiri Mestecky
MALT consists of the major organized lymphoid structures and inductive sites in the lacrimal, respiratory, and digestive tracts. MALT shares common immunologic characteristics and functions as the initiation site for antigen-specific humoral and cell-mediated immune responses. For the organogenesis of the three well-characterized MALTs, the cellular and molecular tissue genesis appears to be different (Figure 3.4), although they share some common characteristics of the organogenesis process including the necessity of CD3−CD4+CD45+ lymphoid tissue inducer (LTi) cells (or group 3 innate lymphoid cells: ILC3) for the initiation of MALT formation. For the development of LTi cells, transcriptional regulators of core binding factor (CBF) β2 are required, and the lack of CBFβ2 resulted in the deficiency of LTi cells leading to the absence of Peyer's patches, NALT, and TALT structure development.
Treating the Dysmetabolism Underlying Osteoporosis
Published in Kohlstadt Ingrid, Cintron Kenneth, Metabolic Therapies in Orthopedics, Second Edition, 2018
A broad range of cell surface receptors and intercellular skeletal structures including those in the extracellular matrix and the cellular cytoskeleton (integrins, cadherins, and Ca+2 channels), intracellular signaling kinases, prostaglandins, and nitric oxide are intimately involved in the regulation of matrix secretion and mineralization [4]. Many of the messengers involved in mediating bone growth are intimately involved in inflammatory signaling pathways. The interplay of these messages is complex and bidirectional. Many growth factors influence osteoblast formation. Core binding Factor A1 (CBFA1) is a transcription factor expressed in osteoblast progenitors and stromal support cells that has been shown to be important in the control of osteoblast development. It regulates the expression of several osteoblast-specific genes including type 1 collagen, the receptor-activator of NFKappaB (RANK) ligand also called the osteoclast differentiation factor, osteocalcin, osteopontin, and bone sialoprotein.
Identifying prognostic gene panels in acute myeloid leukemia
Published in Expert Review of Hematology, 2023
Joaquin Sanchez-Garcia, Josefina Serrano, Esther Prados de La Torre, Juana Serrano-López, Clara Aparicio-Perez, E Barragán, Pau Montesinos
Core binding factor (CBF) AML (CBF-AML) is characterized by the presence of either t(8;21) (q22;q22) or inv(16) (p13q22)/t(16;16). These aberrations produce RUNX1::RUNX1T1 and CBFB::MYH11 fusion genes which generate abnormal CBF heterodimers with altered DNA binding provoking differentiation arrest and enhanced self-renewal capacity of leukemic cells [37]. CBF-AML encounter for 10–15% of AML and are considered of favorable prognosis due to the high remission rates with cytarabine/anthracycline-based chemotherapy induction (with or without Gentuzumab Ogamizin [GO]), and consolidation with high-dose cytarabine (HDAC)-based regimen, leading to 5 y OS up to 75% [38]. However, clonal interference defined as the presence of multiple mutations in KIT, NRAS, KRAS, FLT3, JAK2, and CBL genes are associated with inferior event-free-survival (EFS), although concurrent mutations in these genes do not modify risk categorization according to ELN2022 [39]. The presence of aberrant transcripts absent in normal hematopoiesis allows for quantitative RT-PCR monitoring of MRD in CBF AML. Data from multiple studies have confirmed the utility of MRD monitoring by standardized quantitative RT-PCR in identifying differences in outcomes [40].
Molecular targets for the treatment of AML in the forthcoming 5th World Health Organization Classification of Haematolymphoid Tumours
Published in Expert Review of Hematology, 2022
Matteo Molica, Salvatore Perrone
Among patients with core binding factor (CBF) AML (i.e. those with RUNX1::RUNX1T1 fusion and CBFB::MYH11 fusion), KIT mutations have been observed in up to 25% of cases and may correlate with significantly lower prognosis compared with KIT–wild-type disease when treated with 7 + 3 induction [86]. Imatinib, dasatinib, and midostaurin show activity against c-KIT, among other targets, so repurposing these drugs in CBF AML seems feasible. In a phase II trial including 89 patients with de novo CBF AML, dasatinib was administered with 7 + 3 induction and high-dose cytarabine consolidation and then pursued for 1 year as maintenance [87]. The 4-year cumulative incidence of relapse was 33% with an event-free survival of 58%; these results appeared superior compared with historical outcomes observed after chemotherapy alone. Interestingly, in patients with CBF AML treated with FLAG in combination with either idarubicin and/or gemtuzumab ozogamicin, the presence of KIT mutations did not correlate with an inferior outcome, indicating that more intensive treatments could favorably impact on the negative prognostic effects of KIT mutations [88].
Chronic myelomonocytic leukemia - a review
Published in Expert Review of Hematology, 2021
Thomas P. Thomopoulos, Anthi Bouhla, Sotirios G. Papageorgiou, Vasiliki Pappa
Once reactive monocytosis is excluded, a thorough assessment for an underlying clonal hematopoietic disorder must be made. Cases of chronic myeloid leukemia (CML) accompanied by marked monocytosis are easily excluded by the absence of BCR-ABL1 fusion gene. In cases of prominent eosinophilia, a myeloid/lymphoid neoplasm with eosinophilia should be excluded, by the absence of PDGFRA, PDGFRB, or FGFR1 rearrangements and PCM1-JAK2 gene fusion, as well [1]. Notably, presence of the ETV6-PDGFRB fusion gene is associated with a CMML-like phenotype with prominent eosinophilia [5]. As core-binding factor acute myeloid leukemia (AML) may be also characterized by monocytosis and eosinophilia, disease-defining rearrangements, including inv(16)(p13.1q22) must also be excluded. Rare cases of BCR/ABL1 negative myeloproliferative neoplasms (MPN) with monocytosis at presentation should also be excluded; presence of JAK2 mutation, or other known driver mutation, thrombocytosis, or elevated levels of hemoglobin, and absence of dysplastic features are clues favoring the diagnosis of a classical MPN. It should be noted that presence of dysplastic features in bone marrow is required for establishment of CMML diagnosis. In cases with minimal or absent myelodysplasia, diagnosis is based on presence of clonal cytogenetic or molecular abnormalities [1]. Based on the peripheral WBC count, CMML cases can be subdivided into myelodysplastic CMML (MD-CMML) and myeloproliferative CMML (MP-CMML) (WBC<13 × 109/L and WBC ≥ 13 × 109/L, respectively) [6].