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. 2015 Jul 13;3:64. doi: 10.3389/fped.2015.00064

Table 3.

The different pathophysiological mechanisms and their relative contributions to inherited bone marrow failure syndromes, severe aplastic anemia, and myelodysplastic syndromes.

Pathophysiological mechanism Inherited bone marrow failure syndromes (IBMFS) Myelodysplastic syndromes (MDS) Severe aplastic anemia (SAA)
Inherited cell-intrinsic defects
  • –

    Causative for all forms of ÍBMFS

  • –

    TP53 activation in FA, DC, and DBA cells results in cell cycle inhibition, senescence, and apoptosis meant to protect from malignant transformation but at the same time contributing to BM failure and pancytopenia (72, 73)
  • –

    Familial cases are caused by RUNX1 or GATA2 mutations leading to deregulation of the stem and progenitor cell function (74, 75)

  • –

    No inherited mutations are known for sporadic cases
  • –

    No evidence
Acquisition of driver mutations
  • –

    Secondary evolution to MDS and/or AML (65)

  • –

    Transformation driven by cumulative injury of proliferating cell (e.g., accumulation of DNA damage or chromosomal instability) (64)

  • –

    Compensatory proliferation and selective pressure in pancytopenic patients contribute to transformation (64)
  • –

    Driving force for MDS development and evolution to AML

  • –

    Typical driver mutations conferring clonal advantages affect the ASXL1, EXH2, IDH1, IDH2, KRAS, NRAS, and TET2 genes (76)

  • –

    Such mutations can result in clonal hematopoiesis even before overt MDS and AML occurs (77)

  • –

    Also, familial MDS forms require second hits (e.g., monosomy 7 in patients with GATA2 mutation or loss of heterozygosity in patients with RUNX1 mutations) (78, 79)
  • –

    Secondary evolution to MDS

  • –

    Critical drivers of clonal evolution are compensatory proliferation in the hypocellular marrow and immune escape (64)

  • –

    Characteristic clonal findings: PNH clones with PIGA mutations, deletion of (antigenic) HLA alleles by loss of the chromosomal arm 6p or typical MDS mutations (ASXL1, DNMT3A, TET2, and others) (80–82)
Autoimmunity
  • –

    No contribution reported (83)
  • –

    Clonal T cells were found in MDS patients. Conflicting results indicate that they are either derived from the MDS clone or have been induced by antigenic mutations in MDS cells (84, 85)

  • –

    Approximately 10% of MDS patients have autoimmune-inflammatory manifestations, but the pathophysiological relationship between MDS and autoimmunity remains unclear (86)

  • –

    Some patients show hematological recovery upon immunosuppressive therapy (87)
  • –

    Primary event for SAA

  • –

    Mediated mainly by CD8+ cytotoxic T and Th1 cells that are recruited to the BM (88, 89)

  • –

    Association with certain HLA alleles (90, 91)

  • –

    Autoantibodies have been identified but their significance remains unclear (92, 93)

  • –

    Patients show a good response to immunosuppressive therapy (94, 95)
Inflammatory signaling
  • –

    Inflammation and infectious diseases are thought to accelerate BM failure. Repeated interferon stimulation induces BM failure in a Fanconi mouse model (96)

  • –

    Cytokines induce proliferation and subsequent exhaustion of stem cells. Cycling stem cells get more susceptible toward apoptosis (96, 97)
  • –

    Overproduction of cytokines (i.e., TNFα and IFNγ) by the stem cell niche contributes to apoptosis of MDS cells (98)
  • –

    Th1-shifted cytokine secretion with (i.e., IFNγ, TNFα, and IL-2) contributes to disease pathogenesis by suppressing hematopoiesis (99–101)
Deregulation of the stem cell niche
  • –

    There is evidence that the function of the stem cell niche is compromised because of the underlying genetic mutation (102, 103)

  • –

    However, allogeneic stem cell transplantation can correct all hematological symptoms indicating a minor contribution to disease by the microenvironment
  • –

    Microenvironmental deregulation contributes to pathogenesis (98, 104)

  • –

    In animal models, niche alterations can be sufficient to induce MDS (i.e., by Dicer mutations) (105)

  • –

    Clonal hematopoiesis remodels the niche: in MDS xenograft models, healthy mesenchymal stromal cells cotransplanted with MDS cells adopt molecular features observed in mesenchymal stromal cells derived from MDS patients (106)
  • –

    There is evidence that the stem cell niche might contribute to T cell activation; the results however are conflicting (88)

AML, acute myeloid leukemia; BM, bone marrow; DBA, Diamond Blackfan anemia; DC, dyskeratosis congenita; FA, Fanconi anemia; PNH, paroxysmal nocturnal hemoglobinuria; SDS, Shwachman Diamond syndrome.