remission and in subsequent progression on
suggest that such analysis of the HSC com-
partment could be performed on MDS pa-
tients as both a metric for monitoring response
and as a biomarker for development of tar-
geted therapeutics. This further raises the
possibility of whether the reason current treat-
ment strategies are unable to cure these pa-
tients is the direct result of their inability to
eliminate the residual, clonally abnormal
The big remaining question is whether
MDS LT-HSCs, CMPs, and GMPs have
capability to self-renew in vitro and in vivo,
and if so, by what molecular mechanisms. A
few studies to date suggest that phenotypic
stem and progenitor cell compartments con-
tain leukemia initiating cells in MDS.
also be worth evaluating whether MDS GMPs
may serve as a reservoir for disease progression
to AML, because a recent study found that
AML can arise from GMP-like stem cells.
Lastly, interrogation of the precise molecular
switches that control this lineage-dependent
differentiation block in low- versus high-risk
MDS patients will be of great interest and
could represent a turning point in therapeutic
strategies for the disease. It would also be in-
teresting to know whether such changes occur
before disease onset, potentially predisposing
to low- versus high-risk MDS, or arises as part
of disease progression.
The observation that a small pool of
cancer-initiating stem cells cannot be readily
eliminated by conventional cytotoxic therapies
appears to be something of a common theme
among a variety of cancers. In this regard,
MDS is another in the queue where efforts are
needed for targeting stem cells. Consequently,
ongoing efforts to better understand the mo-
lecular pathways that regulate disease-
initiating cells will potentially have further
implications for the development of future
targeted therapies in a variety of cancers.
Overall, the study by Will and colleagues pro-
vides the impetus for deﬁning the genetic and
epigenetic events governing HSC and
progenitor-cell resistance to therapy and their
role in disease progression.
Conﬂict-of-interest disclosure: The author
declares no competing ﬁnancial interests. ■
1. Will B, Zhou L, Vogler TO, et al. Stem and progenitor
cells in myelodysplastic syndromes show aberrant stage-
speciﬁc expansion and harbor genetic and epigenetic altera-
tions. Blood. 2012;120(10):2076-2086.
2. Nilsson L, Astrand-Grundstrom I, Arvidsson I, et al.
Isolation and characterization of hematopoietic progenitor/
stem cells in 5q-deleted myelodysplastic syndromes: evi-
dence for involvement at the hematopoietic stem cell level.
3. Tehranchi R, Woll PS, Anderson K, et al. Persistent
malignant stem cells in del(5q) myelodysplasia in remission.
N Engl J Med. 2010;363(11):1025-1037.
4. Nilsson L, Eden P, Olsson E, et al. The molecular sig-
nature of MDS stem cells supports a stem-cell origin of 5q
myelodysplastic syndromes. Blood. 2007;110(8):3005-3014.
5. Goardon N, Marchi E, Atzberger A, et al. Coexistence
of LMPP-like and GMP-like leukemia stem cells in acute
myeloid leukemia. Cancer Cell. 2011;19(1):138-152.
6. Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte-
macrophage progenitors as candidate leukemic stem cells in
blast-crisis CML. N Engl J Med. 2004;351(7):657-667.
7. Figueroa ME, Skrabanek L, Li Y, et al. MDS and sec-
ondary AML display unique patterns and abundance of
aberrant DNA methylation. Blood. 2009;114(16):3448-
8. Jiang Y, Dunbar A, Gondek LP, et al. Aberrant DNA
methylation is a dominant mechanism in MDS progression
to AML. Blood. 2009;113(6):1315-1325.
9. Nilsson L, Astrand-Grundstrom I, Anderson K, et
al. Involvement and functional impairment of the
CD34(⫹)CD38(-)Thy-1(⫹) hematopoietic stem cell
pool in myelodysplastic syndromes with trisomy 8.
10. Krivtsov AV, Twomey D, Feng Z, et al. Transforma-
tion from committed progenitor to leukaemia stem cell initi-
ated by MLL-AF9. Nature. 2006;442(7104):818-822.
Comment on Gallagher et al, page 2098
Mutation associations in RA-deﬁant APL
Sai-Juan Chen SHANGHAI INSTITUTE OF HEMATOLOGY
One-quarter of acute promyelocytic leukemia (APL) patients develop resistance to
all-trans retinoic acid (ATRA)/chemotherapy (CT). In this issue of Blood,
Gallagher et al report the associations of PML-RAR␣ mutations, FLT3 mutations,
and additional chromosome abnormalities (ACAs) in relapsed APL.
ntrinsic or acquired resistance to anticancer
drugs can arise from a variety of factors in-
cluding the development of mutations in drug
targets and additional genetic abnormalities.
In APL, which is driven by the t(15;17)–
generating PML-RAR␣, ATRA in combina-
tion with CT achieves a complete remission
rate of 90% and a 5-year disease-free survival
However, ATRA resistance has
been reported for 2 decades and was shown to
be associated with increased catabolism and
decreased delivery to cell nucleus of ATRA, as
well as mutations in the ligand-binding do-
main (LBD) of the RAR␣ portion of the fusion
In this study, Gallagher et al further
dissect the potential association of PML-
RAR␣ LBD mutations (PR␣/LBD
mutations, and ACAs in relapsed APL on
ATRA/CT (see ﬁgure).
The authors show that among 45 relapsed
patients from the ATRA/CT treatment
group, 18 cases harbor PR␣/LBD
7 of whom (39%) relapsed more than 30 days
after last ATRA dose (off ATRA) selection
pressure, suggesting a possible active role of
. Indeed, Gallagher et al observed
in 2 cases the selection of a pre-existing mutant
subclone by ATRA that lead to relapse on or
off ATRA treatment.
the incidence and quantitation of FLT3-
are not increased during relapse with
out any evidence of inﬂuence of ATRA treat-
ment. The fact that all FLT3-ITD
who relapsed off ATRA lacked PR␣/LBD
and most FLT3-ITD
patients (83%) who
relapsed on ATRA had a coincident PR␣/
, suggests that ATRA could not elimi
nate the double-mutant subclone. Exclusive
ACAs are identiﬁed at diagnosis, and are sig-
niﬁcantly increased (2-fold) at relapse (29% to
62%). Structural chromosome changes are
predominantly newly present at relapse and
differ from ACA at diagnosis. Interestingly,
despite the heterogeneity of ACAs, they are
associated with a phenotype of pWBC
L-isoform, if relapse occurred off ATRA.
as a mechanism leading to off-
ATRA disease progression may be proved by
the observation that ACA-PR␣/LBD
negatively associated with FLT3-ITD
which presents an opposite phenotype of pW-
and S-isoform. However, in on-ATRA
relapsed patients, the above associations are
not apparent, suggesting a distinct different
mechanism of resistance and progression. In
prognostic analysis, only the presence of ACA
at relapse is associated with reduced postre-
lapse outcome. In the patients with PR␣/
6 SEPTEMBER 2012 I VOLUME 120, NUMBER 10 1969