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Chapter 28 Thrombocytopoiesis 347

development. Megakaryocytes from these animals have a 200-fold Relationship Between Megakaryocytes and HSCs
increased sensitivity to GM-CSF, suggesting dysregulation of signal-
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ing pathways. Similar megakaryocytic hyperplasia and thrombocytosis Megakaryocytes and HSCs share a striking number of similarities.
occur in mice containing germline c-Myb mutations that disrupt This includes common signaling pathways (TPO signaling), surface
binding the transcriptional coactivator p300. Thus c-Myb may play receptors (CD41, CD150, CXCR4, TPO receptor), and transcrip-
an important negative regulatory function in megakaryocytopoiesis tion factors (RUNX1, GATA2, TAL1, ETV6, and MEIS1). Recent
and thrombocytopoiesis. work has also uncovered a close hierarchical developmental relation-
ship between HSCs and megakaryocytes, where MkP cells can
develop directly (or close to directly) from HSCs. Lastly, HSCs and
Megakaryocyte Enhancesome Complex megakaryocytes share a common niche at the BM vascular sinusoids,
where they physically contact one another. One recent study also
A number of biochemical and genome-wide chromatin occupancy suggests that megakaryocytes are necessary for HSC function. The
studies have provided evidence for physical and functional interac- teleologic explanation for such a close relationship between HSCs
tions between a core set of megakaryocyte transcription factors that and megakaryocytes remains to be elucidated.
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includes GATA1, GATA2, Fli-1, RUNX1, and SCL/TAL1. This
suggests that a specific “enhancesome complex” involving these
factors drives megakaryocyte-specific gene expression. MEIS1, Gfi1b
and NF-E2 p45 likely act independently of this complex.
Inherited Causes of Thrombocytopenia
Although the most common cause of thrombocytopenia is ITP, it is
MICRORNAS IN MEGAKARYOCYTOPOIESIS important to maintain a high index of clinical suspicion for inherited
disorders of thrombocytopoiesis. This is a particular problem because
MicroRNAs (miRNAs) are a class of small (typically 19−25 nucleo- ITP is essentially a diagnosis of exclusion, and many inherited disorders
tide) noncoding RNAs that interact in a sequence-specific manner mimic the macrothrombocytopenia seen in ITP. Making the correct
diagnosis early is paramount, since it may spare patients unneces-
with mRNAs (typically in their 3′ untranslated region in mammals) sary treatment with corticosteroids, other immunosuppressants, and/
and modulate gene expression through either enhanced mRNA decay or splenectomy. In addition, it may be important in guiding deci-
or inhibiting translation. They play roles in development and dif- sions about surveillance for myelodysplasia or leukemia, screening
ferentiation by fine-tuning tissue-specific transcription factor expres- for additional associated clinical problems, and/or possible family
sion. Each miRNA can have multiple target genes, and conversely, planning. Obtaining a careful family history, and sometimes obtaining
each mRNA can be subject to regulation by multiple miRNA species. blood counts of first-degree relatives, is important in fully evaluating
In addition, the transcription of miRNAs themselves are mediated patients with chronic thrombocytopenia. Associated abnormalities may
by RNA polymerase II and are subject to control by transcription provide important clues to the presence of a nonimmune familial
factors. Therefore complex regulatory networks can exist between thrombocytopenia. For instance, associated erythroid abnormalities
and/or an X-linked inheritance pattern (GATA1, FLNA, WASP muta-
miRNAs and transcription factors. A number of miRNAs have been tions) (obligate female carriers may have dimorphic populations of
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shown to influence thrombopoiesis. miR-150 enhances megakaryo- platelets); leukocyte Döhle bodies, +/− nephritis, sensineural hearing
cytopoiesis at the expense of erythropoiesis, suggesting a critical role loss, and early-onset cataracts (Myh9 mutations); family history of
in the cell fate decision of bipotent MEP cells. This is mediated, at myelodysplasia or myeloid leukemia (RUNX1, ANKRD26, and ETV6
least in part, via targeting the 3′-UTR of c-MYB mRNA transcripts. mutations); developmental delay, congenital cardiac anomalies, hand/
TPO signaling increases miR-150 levels. miR-155 inhibits mega- face dysmorphogenesis (Paris-Trousseau/Jacobsen syndrome; Fli-1
karyocytopoiesis by targeting ETS1 and MEIS1 transcription factors. [ETS-1] mutations); bleeding diathesis out of proportion to degree
Other miRNAs have been implicated in controlling thrombopoiesis, of thrombocytopenia (Bernard-Soulier syndrome). A superb review of
but the evidence supporting a functional role is not as strong as for inherited thrombocytopenias and an excellent diagnostic algorithm
has been provided by Balduini et al. Table 28.1 summarizes genes
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miR-150 and miR-155. miRNAs are also present in platelets. Further involved in normal thrombopoiesis that are known to be mutated in
studies are needed to examine their potential role in platelet activa- human platelet disorders.
tion and function.

TABLE Genetic Causes of Human Thrombopoiesis Disorders
28.1
Disease Inheritance Mutated Gene Theme Comments Diagnosis
Thrombocytopenic
Large Platelets
MYH9-related disease AD MYH9 Cytoskeletal Can include nephritis, Myh9 immunofluorescence;
defect sensorineural hearing loss, DNA sequencing
cataracts, Dohle bodies in
granulocytes. Mild bleeding
tendency.
Paris-Trousseau; AD Large deletions Transcription Cardiac and facial anomalies, ± FISH
Jacobsen syndrome at 11q23; factor developmental delay. Mks/
likely FLI1 platelets with giant alpha
or ETS1 granules.
gene
Bernard-Soulier AR-AD GPIba, GPIb Glycoprotein Giant platelets, bleeding diathesis Platelet aggregation
syndrome receptor for in biallelic forms (absent response to
vWF ristocetin); flow
cytometry

Continued