LETTER
LETTER
Reprogramming of B cell acute lymphoblastic leukemia cells: Do we need to shoot a moving target? In a recent paper, McClellan et al. (1) report that blasts from some precursor B cell acute lymphoblastic leukemia (B-ALL) cases transdifferentiate (reprogram) into nonmalignant cells. Although showing induced reprogramming in both Philadelphia chromosomepositive (Ph+) and Ph− cases, the authors concentrate on Ph+ leukemias, proposing reprogramming to be a possible therapeutic modality for this high-risk group of B-ALLs. Although the findings are highly interesting and relevant, we would like to raise several points of concern. The authors report that reprogrammed cells resemble normal macrophages based on mostly descriptive observations. Importantly, the authors claim that those differentiated cells lose leukemogenicity based on xenotranplantation experiments. We would like to point out that modeling myeloid malignancies in nonobese diabetic (NOD)– SCID or NOD/SCID/IL2R-γ–null (NSG) mouse strains is still considered a challenge and next-generation humanized mice models need to be developed (2). To conclude that cells lose leukemogenicity thus appears to be speculative. The engraftment levels might not be attributable solely to leukemogenecity of transplanted cells but could also be a function of cell homing and their ability to interact with host microenvironment. This is of even greater importance in the case of i.v. injection (used by McClellan et al.) compared with orthotopic intrafemoral technique (3). The suggestion that differentiation of these blasts could be exploited therapeutically may be preliminary. We have recently reported (4) a series of 18 childhood B-ALL cases with
www.pnas.org/cgi/doi/10.1073/pnas.1508680112
similar reprogramming of blasts. In such patients, differentiation occurs during induction chemotherapy and generates an abnormal population that appears to be more resistant to treatment. Furthermore, we observed an overt hematological relapse 8 mo after diagnosis caused by transdifferentiated blasts (4). Although the reprogrammed cells might represent the farthest differentiated cell stage, they should not be viewed just as senescent or incapacitated. Described reprogramming in patients treated with conventional therapy also calls for cautious (re)interpretation of the five patients in the McClellan et al. study containing reprogrammed cells even before start of treatment, especially as two of them did not reprogram after cytokine induction. Furthermore, although in vitro induction indeed leads to reprogramming, there are often high numbers of residual blasts resistant to reprogramming. It was also unclear how to prospectively choose patients who would benefit from transdifferentiating therapy. We, as well as McClellan et al., have failed to find any common underlying genetic aberrations so far. However, in contrast to McClellan et al., we observed consistently CD2 expression on initial blasts. Similarly, we could see raised expression of CCAAT/enhancer binding protein alpha (C/EBPα) not only after reprogramming but already at diagnosis. It might be interesting to explore whether some of those features would define B-ALL group prone to reprogramming instead of concentrating on just Ph+ cases. To conclude, we strongly support the relevance of the observations of McClellan
et al. and are convinced that reprogramming of lymphoblastic cells can occur also under conventional chemotherapy. However, we would challenge the notion that this phenomenon leads to a benign differentiated myeloid populations and thus provides a new therapeutic principle. More research is warranted to address this very important question. Karel Fisera, Lucie Slámováa, Jean-Pierre Bourquinb, Jan Trkaa, Jan Starýa, Ondr ej Hrusáka, and Ester Mejstr íkováa,1 a
Childhood Leukemia Investigation Prague (CLIP), Second Faculty of Medicine, Charles University Prague and University Hospital Motol, 150 06 Prague, Czech Republic; and b Children’s Hospital, University of Zurich, 8032 Zurich, Switzerland 1 McClellan JS, Dove C, Gentles AJ, Ryan CE, Majeti R (2015) Reprogramming of primary human Philadelphia chromosome-positive B cell acute lymphoblastic leukemia cells into nonleukemic macrophages. Proc Natl Acad Sci USA 112(13):4074–4079. 2 Rongvaux A, et al. (2013) Human hemato-lymphoid system mice: Current use and future potential for medicine. Annu Rev Immunol 31:635–674. 3 McKenzie JL, Gan OI, Doedens M, Dick JE (2005) Human shortterm repopulating stem cells are efficiently detected following intrafemoral transplantation into NOD/SCID recipients depleted of CD122+ cells. Blood 106(4):1259–1261. 4 Slamova L, et al. (2014) CD2-positive B-cell precursor acute lymphoblastic leukemia with an early switch to the monocytic lineage. Leukemia 28(3):609–620.
Author contributions: K.F., L.S., J.-P.B., J.T., J.S., O.H., and E.M. wrote the paper. The authors declare no conflict of interest. 1
To whom correspondence should be addressed. Email: ester. [email protected].
PNAS | July 7, 2015 | vol. 112 | no. 27 | E3455
LETTER
Reprogramming of B cell acute lymphoblastic leukemia cells: Do we need to shoot a moving target? In a recent paper, McClellan et al. (1) report that blasts from some precursor B cell acute lymphoblastic leukemia (B-ALL) cases transdifferentiate (reprogram) into nonmalignant cells. Although showing induced reprogramming in both Philadelphia chromosomepositive (Ph+) and Ph− cases, the authors concentrate on Ph+ leukemias, proposing reprogramming to be a possible therapeutic modality for this high-risk group of B-ALLs. Although the findings are highly interesting and relevant, we would like to raise several points of concern. The authors report that reprogrammed cells resemble normal macrophages based on mostly descriptive observations. Importantly, the authors claim that those differentiated cells lose leukemogenicity based on xenotranplantation experiments. We would like to point out that modeling myeloid malignancies in nonobese diabetic (NOD)– SCID or NOD/SCID/IL2R-γ–null (NSG) mouse strains is still considered a challenge and next-generation humanized mice models need to be developed (2). To conclude that cells lose leukemogenicity thus appears to be speculative. The engraftment levels might not be attributable solely to leukemogenecity of transplanted cells but could also be a function of cell homing and their ability to interact with host microenvironment. This is of even greater importance in the case of i.v. injection (used by McClellan et al.) compared with orthotopic intrafemoral technique (3). The suggestion that differentiation of these blasts could be exploited therapeutically may be preliminary. We have recently reported (4) a series of 18 childhood B-ALL cases with
www.pnas.org/cgi/doi/10.1073/pnas.1508680112
similar reprogramming of blasts. In such patients, differentiation occurs during induction chemotherapy and generates an abnormal population that appears to be more resistant to treatment. Furthermore, we observed an overt hematological relapse 8 mo after diagnosis caused by transdifferentiated blasts (4). Although the reprogrammed cells might represent the farthest differentiated cell stage, they should not be viewed just as senescent or incapacitated. Described reprogramming in patients treated with conventional therapy also calls for cautious (re)interpretation of the five patients in the McClellan et al. study containing reprogrammed cells even before start of treatment, especially as two of them did not reprogram after cytokine induction. Furthermore, although in vitro induction indeed leads to reprogramming, there are often high numbers of residual blasts resistant to reprogramming. It was also unclear how to prospectively choose patients who would benefit from transdifferentiating therapy. We, as well as McClellan et al., have failed to find any common underlying genetic aberrations so far. However, in contrast to McClellan et al., we observed consistently CD2 expression on initial blasts. Similarly, we could see raised expression of CCAAT/enhancer binding protein alpha (C/EBPα) not only after reprogramming but already at diagnosis. It might be interesting to explore whether some of those features would define B-ALL group prone to reprogramming instead of concentrating on just Ph+ cases. To conclude, we strongly support the relevance of the observations of McClellan
et al. and are convinced that reprogramming of lymphoblastic cells can occur also under conventional chemotherapy. However, we would challenge the notion that this phenomenon leads to a benign differentiated myeloid populations and thus provides a new therapeutic principle. More research is warranted to address this very important question. Karel Fisera, Lucie Slámováa, Jean-Pierre Bourquinb, Jan Trkaa, Jan Starýa, Ondr ej Hrusáka, and Ester Mejstr íkováa,1 a
Childhood Leukemia Investigation Prague (CLIP), Second Faculty of Medicine, Charles University Prague and University Hospital Motol, 150 06 Prague, Czech Republic; and b Children’s Hospital, University of Zurich, 8032 Zurich, Switzerland 1 McClellan JS, Dove C, Gentles AJ, Ryan CE, Majeti R (2015) Reprogramming of primary human Philadelphia chromosome-positive B cell acute lymphoblastic leukemia cells into nonleukemic macrophages. Proc Natl Acad Sci USA 112(13):4074–4079. 2 Rongvaux A, et al. (2013) Human hemato-lymphoid system mice: Current use and future potential for medicine. Annu Rev Immunol 31:635–674. 3 McKenzie JL, Gan OI, Doedens M, Dick JE (2005) Human shortterm repopulating stem cells are efficiently detected following intrafemoral transplantation into NOD/SCID recipients depleted of CD122+ cells. Blood 106(4):1259–1261. 4 Slamova L, et al. (2014) CD2-positive B-cell precursor acute lymphoblastic leukemia with an early switch to the monocytic lineage. Leukemia 28(3):609–620.
Author contributions: K.F., L.S., J.-P.B., J.T., J.S., O.H., and E.M. wrote the paper. The authors declare no conflict of interest. 1
To whom correspondence should be addressed. Email: ester. [email protected].
PNAS | July 7, 2015 | vol. 112 | no. 27 | E3455
