Sunday, March 29, 2015

Tyrosine kinase hyper-activation rather than its inhibition overcomes acute lymphoblastic leukaemia cells resistance

Acute lymphoblastic leukaemia (ALL) in pre-B cells is driven by constitutive activation of tyrosine kinases, such as BCR-ABL1 (Philadelphia chromosome positive) that mimic BCR signalling (that normally serves as a survival signal). For that reason, treatment of ALL usually involves use of tyrosine kinase inhibitors (TKI) such as Gleevec (imatinib). However, frequently ALL cells develop resistance to TKI. 

The authors showed that in vitro assay ALL cells transfected with constitutively active Syk kinase undergo rapid cell death that was actually reversed by imatinib treatment.

Next, the authors showed that BCR-ABL1 transformed ALL cells deficient of signaling molecules with ITIM tail (pecam1, CD300, Lair1) that normally inhibit Syk kinase, undergo rapid cell death.

Further experiments revealed that inhibitory phosphatases, SHP1 (ptpn6) and SHIP1 (inpp5d), downstream of ITIM signalling contributed to ALL cell survival via Syk inhibition.

Finally, the authors showed that use of small molecule inhibitor of SHIP1, 3AC, could lead to rapid ALL cell death due to Syk hyper-activation

In summary, these results showed that even ALL cell still retain sensitivity to BCR negative selection when over-activated. Initially, mutation in BCR-ABL1 make pre-B cells to receive constitutive survival signal. However, additional activation of Syk kinase would push overall signalling within ALL to the threshold of negative selection and to the ultimate ALL cell death. Thus, combining of Gleevec with 3AC-like drugs would provide additional safeguards to prevent the emergence of resistant ALL clones and dramatically improve survival of ALL patients.   

David Usharauli

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