High levels of the adhesion molecule CD44 on leukemic cells generate acute myeloid leukemia relapse after withdrawal of the initial transforming event.
Multiple genetic hits are detected in patients with acute myeloid leukemia (AML). To investigate this further, we developed a tetracycline-inducible mouse model of AML, in which the initial transforming event, overexpression of HOXA10, can be eliminated. Continuous overexpression of HOXA10 is required to generate AML in primary recipient mice, but is not essential for maintenance of the leukemia. Transplantation of AML to secondary recipients showed that in established leukemias, ∼80% of the leukemia-initiating cells (LICs) in bone marrow stopped proliferating upon withdrawal of HOXA10 overexpression. However, the population of LICs in primary recipients is heterogeneous, as ∼20% of the LICs induce leukemia in secondary recipients despite elimination of HOXA10-induced overexpression. Intrinsic genetic activation of several proto-oncogenes was observed in leukemic cells resistant to inactivation of the initial transformation event. Interestingly, high levels of the adhesion molecule CD44 on leukemic cells are essential to generate leukemia after removal of the primary event. This suggests that extrinsic niche-dependent factors are also involved in the host-dependent outgrowth of leukemias after withdrawal of HOXA10 overexpression event that initiates the leukemia.
Molecular Medicine and Gene Therapy, Division of Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology and Cell Therapy, Lund University Hospital, Lund, Sweden.
R
R
Quéré
S
S
Andradottir
A C M
AC
Brun
R A
RA
Zubarev
G
G
Karlsson
K
K
Olsson
M
M
Magnusson
J
J
Cammenga
S
S
Karlsson
D000818:Animals; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000502:physiology*; D018960:Hyaluronan Receptors / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000502:physiology; D011519:Proto-Oncogenes; D012008:Recurrence
C476399:Cd44 protein, mouse; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; C092119:Hoxa10 protein, mouse