The ITIM-containing receptor LAIR1 is essential for acute myeloid leukaemia development.
Conventional strategies are not particularly successful in the treatment of leukaemia, and identification of signalling pathways crucial to the activity of leukaemia stem cells will provide targets for the development of new therapies. Here we report that certain receptors containing the immunoreceptor tyrosine-based inhibition motif (ITIM) are crucial for the development of acute myeloid leukaemia (AML). Inhibition of expression of the ITIM-containing receptor LAIR1 does not affect normal haematopoiesis but abolishes leukaemia development. LAIR1 induces activation of SHP-1, which acts as a phosphatase-independent signalling adaptor to recruit CAMK1 for activation of downstream CREB in AML cells. The LAIR1-SHP-1-CAMK1-CREB pathway sustains the survival and self-renewal of AML stem cells. Intervention in the signalling initiated by ITIM-containing receptors such as LAIR1 may result in successful treatment of AML.
Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Xunlei
X
Kang
Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Zhigang
Z
Lu
1] Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] School of Life Science and Medicine, Dalian University of Technology, Panjin, Liaoning 124221, China.
Changhao
C
Cui
Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Mi
M
Deng
Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Yuqi
Y
Fan
Department of Hematopathology, Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Baijun
B
Dong
Department of Laboratory Medicine, Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Xin
X
Han
Department of Physiology and Pharmacology, Oregon Health and Science University Knight Cancer Institute, Portland, Oregon 97239, USA.
Fuchun
F
Xie
Cell and Developmental Biology, Oregon Health and Science University Knight Cancer Institute, Portland, Oregon 97239, USA.
Jeffrey W
JW
Tyner
Receptor Cell Biology Section, National Institute of Allergy and Infectious Diseases, NIH, Rockville, Maryland 20852, USA.
John E
JE
Coligan
Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Robert H
RH
Collins
Department of Physiology and Pharmacology, Oregon Health and Science University Knight Cancer Institute, Portland, Oregon 97239, USA.
Xiangshu
X
Xiao
1] Department of Hematopathology, Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA [2] The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.
M James
MJ
You
Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Cheng Cheng
CC
Zhang
D000328:Adult; D000368:Aged; D020816:Amino Acid Motifs; D000818:Animals; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D055815:Young Adult
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D011971:Receptors, Immunologic; C108073:leukocyte-associated immunoglobulin-like receptor 1; C517596:CAMK1 protein, human; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6