Isolated Hoxa9 overexpression predisposes to the development of lymphoid but not myeloid leukemia

Abstract

Hoxa9 is expressed in hematopoietic stem and progenitor cells although this expression is usually diminished as these cells undergo differentiation. In addition, aberrant expression of Hoxa9 is strongly associated with both T-cell and myeloid leukemia in mice and humans. Despite this strong association, enforced expression of Hoxa9 in murine bone marrow or thymus has only shown a modest ability to transform cells. To investigate this question, we used Vav regulatory elements to generate a transgenic mouse that targets Hoxa9 overexpression to all hematopoietic tissues. High level expression of the Hoxa9 transgene in the hematopoietic compartment was associated with embryonic lethality, as no pups from founders that expressed high levels of the transgene were born live. However, offspring of an additional founder line, which expressed lower levels of Hoxa9, developed a precursor T cell lymphoblastic leukemia/lymphoma (pre-T LBL), accompanied by spontaneous Notch1 mutations. In contrast to most murine models of leukemia associated with Hoxa9 overexpression, the Vav-Hoxa9 mice did not overexpress other Hoxa cluster genes, mir196b (a microRNA which is embedded in the Hoxa locus), Meis1, or Pbx3. The Hoxa9 transgenic mouse reported here provides a suitable system for the study of Hoxa9 collaborators that drive myeloid and lymphoid malignant transformation.

Medial HOXA genes demarcate haematopoietic stem cell fate during human development

“…HOXA genes are dysregulated in leukemias 46 , 47 and HOXA9 has been previously implicated in mouse foetal HSC self-renewal 32 , 48 . Knockout mice for other Hoxa genes have not revealed strong HSC phenotypes, presumably due to compensation by other Hox genes 49 , 50 .…”

Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation

“…This is fully compatible with the involvement of the HoxA family in stem cell expansion and leukemogenesis. [35][36][37][38] Using RNA interference-based functional screening, Cellot et al 39 identified the H3K4 demethylase JARID1B as a negative regulator of HSC functions among the Jumonji domain-containing family of histone demethylases. The shRNA-mediated knockdown of JARID1B leads to the in vitro expansion of HSCs, which is accompanied by the upregulation of HoxA7, HoxA9, and HoxA10, with preserved long-term reconstitution potential.…”

HOXA9 and MEIS1 gene overexpression in the diagnosis of childhood acute leukemias: Significant correlation with relapse and overall survival

“…Silencing of HOXA9 induces apoptosis in human MLL-positive AML lines, thus signifying its role in repressing apoptosis pathways [12], whereas downregulation of MEIS1 in MLL-rearranged leukemia cell lines results in decreased proliferation and transcriptional repression of cell-cycle entry-related genes [13]. In addition, HOXA9 overexpression has been involved in a subset of lymphoid malignancies, most predominantly precursor T-cell lymphoblastic leukemia/ lymphoma (pre-T LBL) [14,15]. This overexpression is often, but not invariably, accompanied by upregulation of MEIS1, mostly in acute lymphocytic leukemias (ALLs) bearing MLL translocations and to a lesser extent in T-cell ALL characterized by other gene fusions [16][17][18][19].…”