Friday, March 29, 2019

Molecular mayhem - AML relapse after HSCT

Hello,

For many hematological disorders including AML, CLL, ALL HSCT is the only viable therapeutic option when cytogenetics are not conducive for chemotherapeutic agents. However subsequent relapses are not uncommon which are due to subtle molecular alterations because of underlying and acquired mutations.

1) ROLE OF MHC COMPLEX
Tumor cells often undergo copy number variant loss of heterozygosity at MHC loci resulting in absence of incompatible MHC complexes that can present antigens to T cells.
Also, NK cells can't recognize such cells since it's copy neutral defect, so MHC complexes are still present on tumors to inhibit NK cells.

2) IMMUNE CHECKPOINTS
Upregulation of PD-1 and CD47 is quite commonly documented serving to paralyze lymphocytes and macrophages.
It is supposedly due to JAK2 V617F mutations which via activation of STAT3 and STAT5 serves to upregulate transcription of PD-1 and CD47 by phosphorylating their respective promoters.
Others like CD155 , VISTA and B7 also play a role.

3) ROLE OF INFLAMMATORY AND ANTI-INFLAMMATORY CYTOKINES
Upregulated production of TGF-beta and IL-10 results in dampening of immune responsiveness.
Due to FLT3-ITD there is increased synthesis of ATF4 (Activating ranscription factor 4) which inhibits IRF7 (Interferon regulating factor 7) ultimately resulting in reduced production of IL-15 which is instrumental for functioning of NK cells and memory T cells.
Similarly downregulation of GM-CSF and IFN-gamma has been implicated.

4) ROLE OF ENZYMES
Indolamine 2-3 dioxygenase upregulation results in enhanced synthesis of immunosuppressive metabolite Kynurenine.
CD73 and CD39 being ectonucleotidase and ectonucleoside triphosphate hydrolase respectively, increases the adenosine production from AMP and ADP which is an immunosuppressant.

Targeted molecular therapies like sorafenib for FLT3-ITD and ipilimumab as immune checkpoint blocker have been successful in inducing remission in events of relapses attesting to above mechanisms.

-Kirtan Patolia

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