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Figure 3. Role of autophagy in plasma cell ontogeny and malignancy. Differentiating plasma cells and MM cells induce autophagy to
restrict the ER and downregulate BLIMP-1 expression to decrease immunoglobulin synthesis and deal with excessive proteotoxic stress.
Autophagy is also essential for the survival and maintenance of memory B cells and BM long-lived plasma cells. In MM, induction of
autophagy has been linked with bortezomib resistance. Image adapted from Milan et al. [60]

Indeed, sensitivity of MM to PI is determined by a combination of Ig secretory load, protein degradation
capacity, and commitment to plasma cell maturation; which, taken together, suggests that being an ASC
confers this unique susceptibility to MM [56-59] .

While autophagy does not directly dispose of misfolded immunoglobulins, plasma cells deficient in
autophagy had greater energy imbalance, enhanced immunoglobulin synthesis, reduced intracellular
[52]
ATP, and elevated ER stress . Consistent with this, autophagy-deficient plasma cells displayed higher
[52]
expression of BLIMP-1 and XBP1 with corresponding increase in ER size [Figure 3] . These findings
suggest that autophagy not only facilitates the acquisition of an Ig-secretory phenotype in the in pre-
plasma cells, but also serves to limit the overproduction of Ig and maintain cellular ATP levels to ensure
[60]
survival in differentiated plasma cells [Figure 3] . Autophagy also plays an important role in the removal
of misfolded protein aggregates which, due to steric hindrance, are unable to be efficiently degraded by the
[61]
proteasome . Failure to dispose of misfolded protein aggregates results in proteotoxic stress and induction
[62]
of terminal ER stress .

AUTOPHAGY IN MM
Autophagy is necessary for the differentiation and maintenance of antigen-specific long-lived plasma cells,
the physiologic counterpart to MM cells. As MM cells retain many characteristics of the original plasma
cell clone such as Ig secretion and an enlarged cytoplasm and ER, it is reasonable to hypothesize that
autophagy might also play a role in MM proteostasis and survival.

Indeed, MM cells exhibit higher levels of basal autophagy compared to other tumors, including
lymphoma derived from earlier B-cell progenitors, and autophagy is necessary for the survival of MM
[64]
cells . Disruption of autophagy through BECLIN-1 knockdown or pharmacologic inhibition (with
3-methyladenine and/or chloroquine) causes MM cell apoptosis [65,66] . Basal autophagy is hypothesized to