Editors' ChoiceCancer

Mi Casa No Es Su Casa

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Science Translational Medicine  20 Nov 2013:
Vol. 5, Issue 212, pp. 212ec193
DOI: 10.1126/scitranslmed.3007984

A major roadblock to eradicating a patient’s cancer is minimal residual disease, the population of tumor cells left behind after therapy that may initiate new tumors. These cell populations are high-value targets, but developing strategies to eradicate residual tumor cells requires knowing where they live. Acute myeloid leukemia (AML) stem cells occupy the same niches as their normal hematopoietic stem cell (HSC) counterparts, and combinatorial therapies that draw residual leukemic cells out of these niches by exploiting the same signals known to mobilize HSCs have proven to be a particularly successful strategy to sensitize AML cells to chemotherapy. Because chronic myelogenous leukemia (CML) cells also seek refuge in bone marrow niches, a logical and attractive notion was that similar means could be used to target CML cells as well.

Now, Krause and colleagues offer provocative evidence that the niches occupied by leukemia stem cells in AML and CML are not one and the same. Using mutant mice (Col1-caPPR) with an enhanced bone-remodeling phenotype caused by elevated parathyroid hormone signaling, the authors demonstrated that whereas BCR-ABL1–induced CML was significantly attenuated in these mice, engraftment of MLL-AF9­–induced AML cells increased, resulting in diminished downstream survival. These results extended also to human specimens: Bone marrow cells from CML patients engrafted with significantly poorer efficiency in mutant mice with the enhanced bone-remodeling phenotype as compared with wild-type mice. Osteoclast expansion in mutant mice caused elevated levels of transforming growth factor–β1 (TGF-β1) in the bone marrow, and the divergent response of CML and AML cells traced back to differential response to TGF-β1 signaling. Specifically, CML cells responded to exogenous TGF-β1 by reducing proliferation, whereas AML cells were unaffected either because of reduced TGF-β1 receptor expression or higher levels of baseline pSMAD signaling.

The implications of this study are numerous. Most relevant is that application of parathyroid hormone may sensitize residual CML cells to chemotherapy (analogous to the use of CXCR-4 inhibitors or G-CSF for AML, which are already in clinical trials) by mobilizing them from the niches they reside in. Also interesting is that whereas osteoclast expansion compromises CML niches, it may expand AML niches, explaining the enhanced engraftment that occurred in this model. At the very least, these data point to differential recognition of the same signaling in these distinct cell populations (evidenced by their divergent response to TGF-β1) but may point also to distinct niches that AML and CML cells occupy. In this light, a more detailed cellular analysis of the microenvironment that residual CML cells occupy after therapy will provide clues of extracellular factors that can be targeted to mobilize residual CML cell populations further. The involvement of TGF-β1 implies that nonmyelinating Schwann cells (a significant source of TGF-β1 in the bone marrow) may be a great place to start.

D. S. Krause et al., Differential regulation of myeloid leukemias by the bone marrow microenvironment. Nat. Med. 19, 1513–1517 (2013). [Abstract]

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