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AML1-ETO induced leukemia stem cell self-renewal depends on Plcg1

ABSTRACT: High-resolution proteomic analysis of acute myeloid leukemia (AML) stem cells identified phospholipase C- and Ca++-signaling pathways to be differentially regulated in AML1-ETO (AE) driven leukemia. Phospholipase C gamma 1 (Plcg1) could be identified as a direct target of the AE fusion. Genetic Plcg1 inactivation abrogated disease initiation by AE, reduced intracellular Ca++-release and inhibited AE-driven self-renewal programs. In AE-induced leukemia, Plcg1 deletion significantly reduced disease penetrance, number of leukemia stem cells and abrogated leukemia development in secondary recipient hosts. In human AE-positive leukemic cells inactivation of Plcg1 reduced colony formation and AML development in vivo. In contrast, Plcg1 was dispensable for maintenance of murine and human hematopoietic stem- and progenitor cells (HSPCs). Pharmacologic inhibition of Ca++-signaling downstream of Plcg1 resulted in impaired proliferation and self-renewal capacity in AE-driven AML. Thus, the Plcg1 pathway represents a novel specific vulnerability of AE-driven leukemia and poses an important new therapeutic target.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Primary Cell, Stem Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Joanna Kirkpatrick

LAB HEAD: Florian H. Heidel

PROVIDER: PXD011251 | Pride | 2022-01-12

REPOSITORIES: Pride

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			Action	DRS
	171011_JMK_PR_FH_137_DIA.raw	Raw
	171011_JMK_PR_FH_139_DDA1.raw	Raw
	171011_JMK_PR_FH_139_DDA2.raw	Raw
	171011_JMK_PR_FH_139_DDA3.raw	Raw
	171011_JMK_PR_FH_139_DIA.raw	Raw

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AML1-ETO induced leukemia stem cell self-renewal depends on Plcg1

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