Acute myeloid leukemia - Homo sapiens (human)

Curator(s): Joe Strothman

Acute myeloid leukemia (AML) is a disease that is characterized by uncontrolled proliferation of clonal neoplastic cells and accumulation in the bone marrow of blasts with an impaired differentiation program. AML accounts for approximately 80% of all adult leukemias and remains the most common cause of leukemia death. Two major types of genetic events have been described that are crucial for leukemic transformation. A proposed necessary first event is disordered cell growth and upregulation of cell survival genes. The most common of these activating events were observed in the RTK Flt3, in N-Ras and K-Ras, in Kit, and sporadically in other RTKs. Alterations in myeloid transcription factors governing hematopoietic differentiation provide second necessary event for leukemogenesis. Transcription factor fusion proteins such as AML-ETO, PML-RARalpha or PLZF-RARalpha block myeloid cell differentiation by repressing target genes. In other cases, the transcription factors themselves are mutated.    
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Acute myeloid leukemia - Homo sapiens (human) cluster_node40 Hematopoietic progenitor cell cluster_node36 Anti-apoptosis cluster_node41 Hematopoietic cell lineage cluster_Membrane Membrane cluster_node42 Cell cycle node1 2 node2 1 node3 4 node4 4 node5 3 node6 2 node7 15 DNA0 RAR target genes DNA0->RAR target genes node34 c-Myc DNA0->node34 node10 4 node11 17 node13 8 node14 2 node15 20 node16 32 AML1 DNA4 AML1->DNA4 node27 2 CCAAT/enhancer binding protein (C/EBP),alpha CEBPA CEBPA->node27 CEBPA DNA8 CEBPA->DNA8 node28 PU.1 DNA5 node28->DNA5 node29 AML1-EIO node29->CEBPA node29->node28 node29->DNA4 DNA6 node29->DNA6 PMLRARA PMLRARA->DNA0 PMLRARA->node28 PMLRARA->DNA6 zinc finger and BTB domain containing 16 ZBTB16 ZBTB16->DNA6 DNA7 ZBTB16->DNA7 node30 2 CyclinA1 CyclinA1->node30 CyclinA1 Proliferation CyclinA1->Proliferation node31 1 node32 9 node33 5 node35 10 DNA1 node39 Anti-Apoptotic Genes DNA1->node39 DNA3 Proliferative Genes DNA3->Proliferative Genes DNA replication helicase 2 homolog (yeast) DNA2 pim-1 oncogene PIM1 DNA2->PIM1 pim-2 oncogene PIM2 DNA2->PIM2 AML1 Target Gene DNA4->AML1 Target Gene node38 PU.1 Target Gene DNA5->node38 Plakoglobin DNA6->Plakoglobin DNA7->CyclinA1 node37 C/EBPA Target Genes DNA8->node37 node36 Anti-apoptosis MTOR Signaling Pathway Apoptosis Differentiation node37->Differentiation RAR target genes->Differentiation AML1 Target Gene->Differentiation node38->Differentiation node18 (M0) node18->AML1 node18->node28 node19 (M1) node19->CEBPA node20 (M2) node20->CEBPA node20->node29 node21 (M3) node21->PMLRARA node21->ZBTB16 node22 (M4) node22->CEBPA node22->node28 node24 (M5) node24->node28 node25 (M6) node25->node28 node17 4E-BP1 Protein Synthesis node17->Protein Synthesis Protein Synthesis->MTOR Signaling Pathway BCL2-associated agonist of cell death BAD BAD->node14 BAD Cell Survival BAD->Cell Survival Cell Survival->Apoptosis CyclinD1 CyclinD1->node32 CyclinD1 node34->node33 c-Myc node34->Proliferation node34->CyclinD1 peroxisome proliferator-activated receptor gamma PPARG node34->PPARG PIM1->node36 PIM1->PIM2 PIM2->node36 Plakoglobin->DNA0 node8 ERK1/2 node8->node7 ERK1/2 node8->DNA3 Proliferative genes fms-related tyrosine kinase 3 FLT3 FLT3->CEBPA FLT3->node28 growth factor receptor-bound protein 2 GRB2 SOS GRB2->SOS SOS->node1 SOS KRAS HRAS NRAS SOS->RAS Hematopoietic progenitors Hematopoietic progenitors->node18 Hematopoietic progenitors->node19 Hematopoietic progenitors->node20 Hematopoietic progenitors->node20 Hematopoietic progenitors->node21 Hematopoietic progenitors->node22 Hematopoietic progenitors->node22 Hematopoietic progenitors->node24 Hematopoietic progenitors->node25 node23 (M4Eo) Hematopoietic progenitors->node23 node26 (M7) Hematopoietic progenitors->node26 IKK IKK->node13 IKK NFKB IKK->NFKB NFKB->node16 NFKB NFKB->DNA1 Anti-apoptotic genes MEK MEK->node6 MEK MEK->node8 +p mechanistic target of rapamycin (serine/threonine kinase) MTOR MTOR->node15 MTOR MTOR->node17 p70S6K MTOR->p70S6K p70S6K->Protein Synthesis PIK3 PIK3->node3 PIK3 PIP3 PIK3->PIP3 PIP3->node5 PIP3 node12 PKB/Akt PIP3->node12 node12->node11 PKB/Akt node12->BAD +p node12->IKK +p node12->MTOR PPARG->node35 PPARG RAF RAF->node10 RAF RAF->MEK +p RAS->node2 RAS RAS->PIK3 RAS->RAF STAT STAT->node4 STAT STAT->DNA2 Jak-STAT signaling pathway TCF TCF->DNA0 TCF->node31 TCF node9 c-KIT node9->GRB2 node9->PIK3 node9->STAT print "