Cancer Cell

Previews

BMP Meets AML: Induction of BMP Signaling

by a Novel Fusion Gene Promotes
Pediatric Acute Leukemia
John D. Crispino1,* and Michelle M. Le Beau2
1Division of Hematology/Oncology, Northwestern University
2Section of Hematology/Oncology, and the Comprehensive Cancer Center
University of Chicago, Chicago, IL 60637, USA
*Correspondence: [email protected]
http://dx.doi.org/10.1016/j.ccr.2012.10.008

In this issue of Cancer Cell, Gruber et al. report that a significant proportion of children with acute megakar-
yoblastic leukemia acquire a translocation that confers enhanced BMP signaling and promotes self-renewal
of hematopoietic progenitors. This study presents novel therapeutic targets that may lead to improved ther-
apies for this aggressive leukemia.

Acute megakaryoblastic leukemia (AMKL) exception is the presence of a recurring mutually exclusive. Surprisingly, seven
is a rare and deadly form of acute myeloid (1;22) translocation, which creates the cases, including three cases with the
leukemia. There are three major subtypes OTT-MAL (or RBM15-MKL1) fusion novel fusion, also contained amplification
of AMKL that differ from one another in unique to pediatric AMKL. This fusion of the Down syndrome critical region,
their genetics and their prognosis: leads to altered expression of serum implying that dysregulation of Hsa21
leukemia found in children with Down response factor target genes and aber- genes contributes to more than just the
syndrome (DS), in children without DS, rant Notch pathway activation (Cheng DS subtype of AMKL (Gruber et al., 2012).
or in adults. Of these groups, the patho- et al., 2009; Mercher et al., 2009). Addi- CBFA2T3 is a member of the ETO
genesis of DS-AMKL has the greatest tionally, rare findings of JAK and MPL family of co-repressors that is expressed
clarity. Nearly 5% of children with mutations have also been observed in in hematopoietic cells and plays a role in
DS-AMKL acquire GATA1 mutations in this group. regulating stem cell quiescence (Chyla
mid-gestation that lead to abnormal To identify new mutations and chromo- et al., 2008). In contrast, the gene encod-
megakaryocyte development. It is be- somal aberrations that define pediatric ing GLIS2, which participates in the regu-
lieved that the combination of a GATA1 AMKL, Gruber et al. (2012; this issue lation of SHH signaling, is not expressed
mutation and aberrant expression of of Cancer Cell) took advantage of next- in hematopoietic cells. However, as a
ERG and DYRK1A, among other genes generation sequencing, a powerful tool consequence of the fusion, the C-terminal
on chromosome 21, promotes a pre- that provides new insights into the zinc finger domain that binds the GLIS
leukemia named transient myeloprolifera- genetics of cancer. Paired-end se- consensus sequence is fused to the
tive disorder (TMD) (Malinge et al., 2012). quencing of a discovery cohort consisting N-terminal CBFA2T3 nervy domain that
Evolution of TMD to AMKL likely requires of 14 pediatric non-DS AMKL patients mediates protein-protein interactions
the acquisition of additional mutations in revealed structural variations that led to and is expressed in blood cells. Gene
genes such as MPL and JAK2, which are novel chimeric transcripts in 12 of the expression studies comparing fusion-
associated with aberrant megakaryopoie- cases. Of note, half of the AMKL cases positive AMKLs against other forms of
sis in the myeloproliferative neoplasms harbored a cryptic inversion on chromo- AML revealed that cases with the fusion
(MPNs). It is also believed that GATA1 some 16 inv(16)(p13.3q24.3), which led showed altered expression of genes in
mutations confer hypersensitivity to treat- to fusion of CBFA2T3 and GLIS2. Two of the BMP, SHH, and WNT pathways. In
ment with cytosine arabinoside, which these cases with the CBFA2T3-GLIS2 particular, marked overexpression of
leads to a favorable outcome (Ge et al., fusion also had a gain of chromosomal BMP2 and BMP4 was observed (Figure 1).
2004). In sharp contrast, adults with arm 21q, a common abnormality in Of note, expression of CBFA2T3-GLIS2
AMKL face a dismal prognosis, with AMKL. Remarkably, after screening a or GLIS2 alone in Drosophila led to
nearly all patients relapsing within one larger validation cohort and other enhanced BMP signaling and the associ-
year of diagnosis (Tallman et al., 2000). leukemia samples, the fusion was de- ated dpp gain-of-function phenotype,
Apart from sporadic mutations in JAK2 tected in 27% of pediatric non-DS AMKL including shortened legs and wing blis-
and MPL, little is known about the genetic cases. The CBFA2T3-GLIS2 fusion was tering (Gruber et al., 2012).
basis of adult AMKL. not observed in adult AMKL nor in any The discovery of this novel recurring
Although there have been many revela- other form of myeloid leukemia. In addi- translocation raises a number of im-
tions about pediatric AMKL in children tion, none of the samples with inv(16) portant questions. First, is the fusion
with DS, much less is known about the (p13.3q24.3) had t(1;22), suggesting that a necessary and/or sufficient factor
etiology of other pediatric cases. One these two recurring translocations are in leukemogenesis? Functional studies

Cancer Cell 22, November 13, 2012 ª2012 Elsevier Inc. 567
 Cancer Cell

Previews

demonstrated that expres- fusion, development of novel

sion of the fusion protein, or therapies is essential. The
GLIS2 alone, led to enhanced observation that a BMP
self-renewal of hematopoi- antagonist disrupts re-plating
etic progenitors in vitro. This of hematopoietic progenitors
phenotype was blocked by suggests that inhibition of
dorsomorphin, a small mole- BMP signaling may provide
cule that interferes with BMP therapeutic benefit. However,
signaling to Smad effectors, additional events that coop-
suggesting that the increased erate with the fusion to drive
expression of BMP down- acute leukemia may circum-
stream of the fusion is vent anti-BMP therapy. Future
essential for the phenotype. preclinical and, if appropriate,
Expression of the CBFA2T3- clinical studies to determine
GLIS2 fusion transcript in the effectiveness of BMP
mice, however, did not lead inhibitors against human
to leukemia, indicating that AMKL are needed.
the fusion protein is not suffi-
cient for leukemogenesis. It is
likely that mutations, which REFERENCES
confer cytokine independent
Figure 1. Model of the Activity of inv(16)(p13.3q24.3) Gene Fusion
growth, such as those in Product in AMKL Cheng, E.C., Luo, Q., Bruscia, E.M.,
Renda, M.J., Troy, J.A., Massaro,
MPL or JAK family members, The CBFA2T3-GLIS2 fusion protein generated by inv(16)(p13.3q24.3) likely
S.A., Tuck, D., Schulz, V., Mane,
cooperate with the fusion to directly activates transcription of activators of BMP signaling BMP2 and
S.M., Berliner, N., et al. (2009). Blood
BMP4 as well as inhibitors of SHH signaling PTCH and HHIP. BMP2/4 may 113, 2826–2834.
promote AMKL. act in an autocrine manner to foster growth of AMKL blasts or may alternatively
Second, is there a contribu- signal in a paracrine manner to hematopoietic progenitors that, in turn, would
Chyla, B.J., Moreno-Miralles, I.,
tion by CBFA2T3 apart from promote the megakaryocytic lineage phenotype of the leukemia. In addition, Steapleton, M.A., Thompson, M.A.,
mutations in MPL or JAK family members confer cytokine independence Bhaskara, S., Engel, M., and Hie-
driving expression of GLIS2 and likely cooperate with the fusion to promote AMKL. bert, S.W. (2008). Mol. Cell. Biol.
in hematopoietic cells? The 28, 6234–6247.
finding that GLIS2 trans-
duced hematopoietic progenitors failed remains to be determined, but the fact that Ge, Y., Jensen, T.L., Stout, M.L., Flatley, R.M.,
to re-plate to the same extent as progen- expression of CBFA2T3-GLIS2 in mice Grohar, P.J., Ravindranath, Y., Matherly, L.H.,
and Taub, J.W. (2004). Cancer Res. 64, 728–735.
itors transduced with the fusion strongly does not confer leukemia suggests that
suggests that there is an additional, as additional events are required for full Greaves, M.F., and Wiemels, J. (2003). Nat. Rev.
yet undefined, contribution by CBFA2T3. transformation. Similar to GATA1 muta- Cancer 3, 639–649.
Alternatively, it is possible that loss of tions, the fusion is not detected in adult
Gruber, T.A., Gedman, A.L., Zhang, J., Koss, C.S.,
the N-terminal amino acids of GLIS2 in AMKL, implying perhaps that necessary Marada, S., Ta, H.Q., Chen, S.-C., Su, X., Ogden,
the fusion may alter GLIS2 function. cooperating events are not possible in S.K., Dang, J., et al. (2012). Cancer Cell 22, this
Third, what is the natural history of the bone marrow progenitors. issue, 683–697.
disease? GATA1 mutations in DS-AMKL Fourth, how does the translocation
Jeanpierre, S., Nicolini, F.E., Kaniewski, B., Du-
originate in the fetal liver and can be de- specifically lead to pediatric AMKL? montet, C., Rimokh, R., Puisieux, A., and Ma-
tected as early as 21 weeks of gestation Previous studies have shown that in- guer-Satta, V. (2008). Blood 112, 3154–3163.
(Taub et al., 2004). However, although creased BMP signaling induces the differ-
GATA1 mutations in DS are suspected to entiation of CD34+ cells to megakaryo- Malinge, S., Bliss-Moreau, M., Kirsammer, G., Die-
bold, L., Chlon, T., Gurbuxani, S., and Crispino,
cause TMD, not all babies with GATA1 cytes (Jeanpierre et al., 2008). This effect J.D. (2012). J. Clin. Invest. 122, 948–962.
mutations show an overt hematopoietic may be the result of upregulation of JAK/
phenotype, and the majority do not go on STAT signaling, as seen in MPNs and Mercher, T., Raffel, G.D., Moore, S.A., Cornejo,
to develop AMKL. This finding is reminis- AMKL with activating mutations in MPL M.G., Baudry-Bluteau, D., Cagnard, N., Jesneck,
J.L., Pikman, Y., Cullen, D., Williams, I.R., et al.
cent of classical studies by Greaves and and JAK family members. However, the (2009). J. Clin. Invest. 119, 852–864.
Wiemels (2003), who showed that chro- details of how activated BMP signaling,
mosomal translocations can be detected downstream of the CBFA2T3-GLIS2 Tallman, M.S., Neuberg, D., Bennett, J.M., Fran-
cois, C.J., Paietta, E., Wiernik, P.H., Dewald, G.,
at birth even in children who do not go on fusion protein, imparts a megakaryocytic Cassileth, P.A., Oken, M.M., and Rowe, J.M.
to develop leukemia. The timing of the phenotype remains a mystery. (2000). Blood 96, 2405–2411.
pediatric non-DS AMKL suggests that Finally, will BMP inhibitors prove to be
the fusion of CBFA2T3 and GLIS2 occurs effective new therapies for AMKL? Given Taub, J.W., Mundschau, G., Ge, Y., Poulik, J.M.,
Qureshi, F., Jensen, T., James, S.J., Matherly,
in utero and within the fetal liver. Whether the poor prognosis of AMKL and, in partic- L.H., Wechsler, J., and Crispino, J.D. (2004). Blood
all instances of the fusion lead to leukemia ular, cases with the CBFA2T3-GLIS2 104, 1588–1589.

568 Cancer Cell 22, November 13, 2012 ª2012 Elsevier Inc.