HIF factors cooperate with PML‐RARα to promote acute promyelocytic leukemia progression and relapse

Abstract

Acute promyelocytic leukemia (APL) is epitomized by the chromosomal translocation t(15;17) and the resulting oncogenic fusion protein PML-RARα. Although acting primarily as a transcriptional repressor, PML-RARα can also exert functions of transcriptional co-activation. Here, we find that PML-RARα stimulates transcription driven by HIF factors, which are critical regulators of adaptive responses to hypoxia and stem cell maintenance. Consistently, HIF-related gene signatures are upregulated in leukemic promyelocytes from APL patients compared to normal promyelocytes. Through in vitro and in vivo studies, we find that PML-RARα exploits a number of HIF-1α-regulated pro-leukemogenic functions that include cell migration, bone marrow (BM) neo-angiogenesis and self-renewal of APL blasts. Furthermore, HIF-1α levels increase upon treatment of APL cells with all-trans retinoic acid (ATRA). As a consequence, inhibiting HIF-1α in APL mouse models delays leukemia progression and exquisitely synergizes with ATRA to eliminate leukemia-initiating cells (LICs).

HIF-1α regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment

“…Although our data indicate that in CLL, HIF-1a causes homing and retention in protective microenvironments, it is interesting to note that in other hematologic malignancies, including multiple myeloma and acute and chronic myeloid leukemia, hypoxia or HIF-1a activity instead induces cell egress and disease dissemination. 3,22,40,41 This difference may be caused by the selectivity of HIF-1a-mediated responses in different cell types, [42][43][44] such that adhesion factors may be regulated by HIF-1a specifically in CLL. Further studies should address in greater detail the specificity of HIF-1a activity in different tumor types, especially if HIF inhibitors will be considered for therapeutic intervention.…”

“…17,18 Constitutive HIF-1a expression was suggested to induce vascular endothelial growth factor (VEGF) upregulation and neoangiogenesis. [19][20][21] However, because HIF-1a regulates a variety of other functions in solid tumors and hematologic malignancies, 1,22,23 we asked whether HIF-1a also controlled other aspects of CLL pathogenesis. Microarray analysis was performed upon stable HIF-1a silencing in the human CLL cell line MEC-1 ( Figure 1A-B), where HIF-1a is constitutively expressed in normoxia and further stabilized by the hypoxia-mimetic agent CoCl 2 ( Figure 1B).…”

Synergistic Leukemia Eradication by Combined Treatment with Retinoic Acid and HIF Inhibition by EZN-2208 (PEG-SN38) in Preclinical Models of PML-RARα and PLZF-RARα–Driven Leukemia

“…Moreover, we found that HIF-1a expression is increased upon ATRA treatment, and mediates ATRA-induced increase in clonogenic activity in APL cells (12,14). Therefore, HIF-1a silencing synergizes with ATRA treatment in vivo to eradicate leukemia-initiating cells (LIC) and prevent leukemia relapse (12).…”

“…APL leukemic mice were obtained as previously described (10,12). Briefly, mice bearing PML-RARa-driven APL were obtained by transduction of Lin-bone marrow cells from 129/ Sv mice with a retroviral vector (pBABE backbone with DNGFR as a reporter) expressing PML-RARa (12).…”

“…In APL, HIF factors cooperate with PML-RARa to promote leukemia progression primarily by mediating APL cell migration, homing to bone marrow, and bone marrow neo-angiogenesis (12,13). Moreover, we found that HIF-1a expression is increased upon ATRA treatment, and mediates ATRA-induced increase in clonogenic activity in APL cells (12,14). Therefore, HIF-1a silencing synergizes with ATRA treatment in vivo to eradicate leukemia-initiating cells (LIC) and prevent leukemia relapse (12).…”