Exovesicular-Shh confers Imatinib resistance by upregulating Bcl2 expression in chronic myeloid leukemia with variant chromosomes

Anusha Anusha,Divya A Gowda,Sitalakshmi Subramanian,Hamza Dalal,Snijesh V P,Sharat Damodar,Krishnamurthy H,Neha Vyas

doi:10.1038/s41419-021-03542-w

Abstract

Chronic myeloid leukemia (CML) patients with complex chromosomal translocations as well as non-compliant CML patients often demonstrate short-lived responses and poor outcomes on the current therapeutic regimes using Imatinib and its variants. It has been derived so far that leukemic stem cells (LSCs) are responsible for Imatinib resistance and CML progression. Sonic hedgehog (Shh) signaling has been implicated in proliferation of this Imatinib-resistant CD34(+) LSCs. Our work here identifies the molecular mechanism of Shh-mediated mutation-independent Imatinib resistance that is most relevant for treating CML-variants and non-compliant patients. Our results elucidate that while Shh can impart stemness, it also upregulates expression of anti-apoptotic protein—Bcl2. It is the upregulation of Bcl2 that is involved in conferring Imatinib resistance to the CD34(+) LSCs. Sub-toxic doses of Bcl2 inhibitor or Shh inhibitor (<<IC50), when used as adjuvants along with Imatinib, can re-sensitize Shh signaling cells to Imatinib. Our work here highlights the need to molecularly stratify CML patients and implement combinatorial therapy to overcome the current limitations and improve outcomes in CML.

Highlights

Chronic myeloid leukemia (CML) is caused mainly due to 9:22 chromosomal translocation
We find that Sonic hedgehog (Shh) is predominantly secreted in CML patientderived bone marrow (BM) plasma on exovesicles for imparting Imatinib resistance
Shh is produced by BM leukemic cells in CML-variants and non-compliant patients Shh signaling has been implicated in Imatinib resistance[10,11,16,17]

Summary

Introduction

Chronic myeloid leukemia (CML) is caused mainly due to 9:22 chromosomal translocation. The resultant BCRABL fusion protein codes for a constitutively active tyrosine kinase, resulting in their uncontrolled cell division. BCR-ABL(+) cells accumulate in the blood—a hallmark of ~90% of CMLs. Since 2001, targeted therapy using tyrosine kinase inhibitor (TKI) drugs (Imatinib and its variants) has been highly successful in eradicating the CD34(–) BCR-ABL(+) cells and has improved outcomes in CML. Chromosomal variants of CML (CML-variants) have been reported in 5–10% of the cases.

Methods

Results

Conclusion