Leukemia (2018) 32:1477–1478
Acute myeloid leukemia
Revisiting thrombocytopenia in acute promyelocytic leukemia
Received: 20 February 2018 / Accepted: 23 February 2018 / Published online: 23 March 2018
© Macmillan Publishers Limited, part of Springer Nature 2018
Acute promyelocytic leukemia (APL), which accounts for
10–15% of acute myeloid leukemia (AML) cases, is one of
the true success stories in oncology, as targeted therapeutic
approaches have converted this former lethal disease into a
disease from which the vast majority of patients is cured.
Historically, this unique and highly lethal leukemia subtype
was characterized by fatal bleeding events as documented
by early studies in the 1950s with median survival rates
often below 1 month . This progress in the clinical
management of APL would not have been possible without
a tremendous progress in understanding the underlying
biology of this distinct leukemia subtype, which paved the
way for developing oncoprotein—targeted approaches .
Recent clinical trials have shown excellent results for low-
or intermediate-risk APL patients receiving a chemo-free
combination of all-trans retinoic acid (ATRA) and arsenic
trioxide (ATO) with an event-free survival and overall
survival at 50 months of 97.3% and 99.2%, respectively .
However, especially in high risk, as well as frail patients
APL still bears considerable early mortality through
hemorrhagic complications caused by the development of a
coagulopathy . The risk of early death from hemorrhage
has been estimated at 5–29% and contributing factors are
abnormal coagulation parameters, including a prolonged
prothrombin time, partial thromboplastin time, decreased
ﬁbrinogen levels, as well as thrombocytopenia. Thrombo-
cytopenia is frequently found in APL patients and together
with the white blood cell count determines the risk group
. Despite the clinically well-documented coagulopathy
and the underlying molecular mechanisms of thrombocy-
topenia, caused by APL cells are not fully understood.
In this issue of Leukemia, Lavallée et al.  reported
on intriguing ﬁndings, characterizing Podoplanin (PDPN), a
gene involved in platelet aggregation, as a protein speciﬁ-
cally expressed in human APL and being able to cause
thrombocytopenia and prolonged bleeding time in a xeno-
graft model of human AML cell lines.
How did they identify PDPN as a key gene in APL?
First, Lavallée et al.  compared the transcript levels
derived from coagulation, ﬁbrinolysis, and platelet ligand
genes between 30 APL and 400 primary AML patients with
various cytogenetics. As previously described, they found
higher levels of tissue factor (TF), annexin A2, and uroki-
nase in APL samples . However, the most signiﬁcantly
differentially expressed transcript was PDPN being almost
exclusively expressed in APL patients. PDPN is a trans-
membrane O-glycoprotein and important for the formation
of lymphatic vessels through interaction with the platelet
receptor CLEC2 inducing platelet aggregation . PDPN
was found to be expressed on 88% of the tested primary
APL cells, including microgranular APL (FAB M3v).
Importantly, the gene was not expressed on any cell of
normal adult hematopoiesis, including normal promyelo-
cytes, highlighting its aberrant expression on human APL.
This observation might facilitate diagnostics in a subfrac-
tion of patients with microgranular APL, for which mor-
phological diagnosis is sometimes difﬁcult. Importantly,
the authors could demonstrate that aberrant expression of
PDPN induces platelet aggregation in vitro, ectopically
expressing PDPN in OCI-AML5 cells and mixing them
with platelet rich plasma. As expected, PDPN expressing
cells showed a much more pronounced platelet-binding
capacity and platelet activation than the control cells.
Similar ﬁndings could be extended to primary APL cells.
In vivo, OCI-AML5 cells overexpressing PDPN led to
thrombocytopenia through platelet consumption and a sig-
niﬁcantly prolonged bleeding time, pointing to its con-
tribution to APL-associated coagulopathy. Coagulopathy
in APL is a complex process and not fully understood.
* Florian Kuchenbauer
* Christian Buske
Department of Internal Medicine III, University Hospital Ulm,
Ulm 89081, Germany
Comprehensive Cancer Centre Ulm, Institute of Experimental
Cancer Research, University Hospital Ulm, Ulm 89081, Germany