Survival signaling in HoxA9/Meis1 AML

Two papers in this issue of Blood address the importance of survival signals in the expansion of myeloid leukemia progenitors in vivo. Morgado and colleagues report the surprising result that FLT3 signaling is completely unimportant, while Jin and colleagues identify a new kinase, Trib1, as a primarily cooperating oncoprotein.

In this issue of Blood, Morgado and colleagues report that FLT3 signaling does not contribute to the survival or growth of leukemic progenitors coexpressing HoxA9 and Meis1. In this murine model, HoxA9 enforces immortal self-renewal of nonleukemic progenitors, and Meis1 activates leukemogenicity and transcription of stem-cell genes including FLT3,¹  suggesting that FLT3 signaling may be critical for the outgrowth of leukemic progenitors. The preponderance of activating mutations in FLT3 in human acute myeloid leukemia (AML) reiterates this idea. By infecting hematopoietic stem cells from wild-type and FLT3^−/− mice with murine stem-cell virus (MSCV) vectors coexpressing HoxA9 and Meis1, and comparing their ability to induce AML in irradiated recipients, Morgado et al found no positive role for FLT3 in the emergence of AML.

In human AML, could FLT3 signaling also play no role in the establishment of primary disease? Is it possible that only activated forms of FLT3 are significant, and then only in the context of augmenting survival and expansion of leukemic blasts in late-stage disease? Recent data from drug trials are not inconsistent with this model, because FLT3 inhibitors have been found to eliminate circulating blasts, which may be “addicted” to FLT3 signaling, but rarely achieve significant reductions in counts of bone marrow blasts.²  But if FLT3 signaling is dispensable, why do other studies in the mouse find it to be important, if not essential?

Palmqvist et al found that expression of FLT3 accelerated the latency of NUP98-HoxA10 AML from 150 to 80 days, and even conveyed leukemia-initiating character to nonleukemic NUP98-HoxA10 progenitor cell lines.³  Wang and Kamps found that in a black/6 background, FLT3^−/− myeloid progenitor cell lines immortalized by HoxA9/Meis1 retrovirus exhibit a longer AML latency (150 days) than their FLT3^+/+ cognates (100 days; G.G.W. and M.P.K., unpublished observation, October 2006). The differential dependence of AML progenitors on FLT3 signaling may be reconciled if proliferation of some AML blasts is driven by compensatory signaling pathways that render FLT3 dispensable (eg, receptor activation by niche cytokines or undiscovered mutations in signaling genes), while that of other AML blasts, such as cultured progenitor lines or subsets of clones that evolve in vivo, is partially or completely dependent on FLT3 signaling because they lack compensatory pathways. But is there evidence that other novel signaling pathways are activated in mouse models of AML, pathways whose activation could also compensate for FLT3 signaling in human AML?

Indeed, in a second article in this issue of Blood, Jin and colleagues report that integration of HoxA9/Meis1 provirus in murine AML models activates transcription of genes that cooperate in leukemogenesis, some of which signal survival and proliferation. They demonstrate that 25% of AMLs activate transcription of Trib1, which encodes a serine/threonine kinase that potentiates cytokine-induced signaling by MAP kinase kinase, a pathway also used by FLT3. An untested possibility is that similar mutations influence the FLT3 dependence of murine HoxA9/Meis1 progenitors and of human AML blasts.

Collectively, both papers suggest that survival pathways used by human AML blasts may be diverse, that clones within a single disease may evolve to rely on different pathways, and that effective AML therapies that target signal transduction pathways may require a combination of drugs that inhibit multiple signaling initiators.