Cbf beta-SMMHC induces distinct abnormal myeloid progenitors able to develop acute myeloid leukemia.
The acute myeloid leukemia (AML)-associated CBF beta-SMMHC fusion protein impairs hematopoietic differentiation and predisposes to leukemic transformation. The mechanism of leukemia progression, however, is poorly understood. In this study, we report a conditional Cbfb-MYH11 knockin mouse model that develops AML with a median latency of 5 months. Cbf beta-SMMHC expression reduced the multilineage repopulation capacity of hematopoietic stem cells (HSCs) while maintaining their numbers under competitive conditions. The fusion protein induced abnormal myeloid progenitors (AMPs) with limited proliferative potential but leukemic predisposition similar to that of HSCs in transplanted mice. In addition, Cbf beta-SMMHC blocked megakaryocytic maturation at the CFU-Meg to megakaryocyte transition. These data show that a leukemia oncoprotein can inhibit differentiation and proliferation while not affecting the maintenance of long-term HSCs.
Kuo
Ya-Huei
YH
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Landrette
Sean F
SF
Heilman
Susan A
SA
Perrat
Paola N
PN
Garrett
Lisa
L
Liu
Pu P
PP
Le Beau
Michelle M
MM
Kogan
Scott C
SC
Castilla
Lucio H
LH
D000208:Acute Disease; D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D001792:Blood Platelets / Q000473:pathology; D049109:Cell Proliferation; D006410:Hematopoiesis; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology*; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011289:Preleukemia / Q000378:metabolism / Q000473:pathology*
C095514:CBFbeta-MYH11 fusion protein; D015514:Oncogene Proteins, Fusion