Common clonal origin of an acute B-lymphoblastic leukemia and a Langerhans' cell sarcoma: evidence for hematopoietic plasticity.
BACKGROUND
The hierarchical organization of hematopoiesis with unidirectional lineage determination has become a questionable tenet in view of the experimental evidence of reprogramming and transdifferentiation of lineage-determined cells. Clinical examples of hematopoietic lineage plasticity are rare. Here we report on a patient who presented with an acute B-lymphoblastic leukemia and developed a Langerhans' cell sarcoma 9 years later. We provide evidence that the second neoplasm is the result of transdifferentiation.


METHODS
B-cell acute lymphoblastic leukemia was diagnosed in an 11-year old boy in 1996. Treatment according to the ALL-BFM-1995 protocol resulted in a complete remission. Nine years later, in 2005, Langerhans' cell sarcoma was diagnosed in a supraclavicular lymph node. Despite treatment with different chemotherapy protocols the patient had progressive disease. Finally, he received an allogeneic peripheral blood stem cell transplant and achieved a continuous remission. Molecular studies of IGH- and TCRG-gene rearrangements were performed with DNA from the Langerhans' cell sarcoma and the cryopreserved cells from the acute B-lymphoblastic leukemia. The expression of PAX5 and ID2 was analyzed with real-time reverse transcriptase polymerase chain reaction.


RESULTS
Identical IGH-rearrangements were demonstrated in the acute B-lymphoblastic leukemia and the Langerhans' cell sarcoma. The key factors required for B-cell and dendritic cell development, PAX5 and ID2, were differentially expressed, with a strong PAX5 signal in the acute B-lymphoblastic leukemia and only a weak expression in the Langerhans' cell sarcoma, whereas ID2 showed an opposite pattern.


CONCLUSIONS
The identical IGH-rearrangement in both neoplasms indicates transdifferentiation of the acute B-lymphoblastic leukemia into a Langerhans' cell sarcoma. Loss of PAX5 and the acquisition of ID2 suggest that these key factors are involved in the transdifferentiation from a B-cell phenotype into a Langerhans'/dendritic cell phenotype. (Clinical trial registration at: Deutsches KrebsStudienRegister, http://www.studien.de, study-ID:8).
Ratei
Richard
R
Department of Hematology, Oncology, and Tumor Immunology, HELIOS Klinikum Berlin-Buch, Berlin, Germany.
Hummel
Michael
M
Anagnostopoulos
Ioannis
I
Jähne
Doris
D
Arnold
Renate
R
Dörken
Bernd
B
Mathas
Stephan
S
Benter
Thomas
T
Dudeck
Oliver
O
Ludwig
Wolf-Dieter
WD
Stein
Harald
H
D054338:Cell Transdifferentiation; D002648:Child; D002999:Clone Cells / Q000473:pathology; D015321:Gene Rearrangement; D006410:Hematopoiesis; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D051797:Inhibitor of Differentiation Protein 2 / Q000032:analysis; D054752:Langerhans Cell Sarcoma / Q000473:pathology*; D015448:Leukemia, B-Cell / Q000473:pathology*; D008297:Male; D016609:Neoplasms, Second Primary / Q000209:etiology / Q000473:pathology; D051757:PAX5 Transcription Factor / Q000032:analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*
C497450:ID2 protein, human; D007143:Immunoglobulin Heavy Chains; D051797:Inhibitor of Differentiation Protein 2; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human