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Deletion of ATG7, a critical component of autophagosome formation, in murine HSCs results in
accumulation of dysfunctional mitochondria, upregulation of oxidative stress and DNA damage, and
[46]
ultimately cell death . Interestingly, aged HSCs were found to maintain a low metabolic state by
upregulating autophagy in order to sustain robust long-term self-renewal potential comparable to young
[44]
HSCs . Downstream of HSCs, autophagy also plays a key role in the development, differentiation, and
[41]
function of erythrocytes, platelets, granulocytes, macrophages, and T cells as summarized in Figure 2 .
Since malignant transformation of HSCs or early progenitors results in leukemia, homeostatic mechanisms;
such as autophagy, that protect HSCs from metabolic, oxidative, and genotoxic stress; are crucial to prevent
[47]
hematopoietic malignancies . Indeed, ATG7 deletion in myeloid cells results in dysregulated and invasive
[42]
myeloproliferation resembling acute myeloid leukemia .
Autophagy in plasma cell ontogeny
Autophagy plays a key role in plasma cell (1) differentiation; (2) survival; and (3) protein quality control.

Autophagy in plasma cell differentiation and survival
B lymphocyte to plasma cell differentiation is controlled by a complex genetic reprogramming system leading
to downregulation of genes involved in the maintenance of B-cell identity [e.g., paired box protein 5 (PAX5),
transcription regulator protein BACH2 (BACH2), B-cell lymphoma protein 6 (BCL6)] and upregulation of
genes involved in terminal differentiation of Ig-secretory plasma cells [e.g., B-lymphocyte-induced maturation
[48]
protein 1 (BLIMP-1), interferon regulatory factor 4 (IRF4), and X-box binding protein 1 (XBP1)] .
Specifically, BLIMP-1 acts as a molecular switch to repress PAX5 and BCL6, and induces XBP1 to promote
antibody production and plasma cell differentiation [49,50] . Interestingly, while BLIMP-1 and IRF4 are
[51]
essential for plasma cell differentiation, only IRF4 is essential for plasma cell survival . Consistent with
this, BLIMP-1 deficient plasma cells remained viable and retained their transcriptional identity but lose the
[51]
ability to secrete Ig .
Beyond epigenetics, autophagy also plays an essential role in plasma cell differentiation and survival
[Figure 3]. Studies have found increased expression of autophagic genes in differentiating plasma cells.
Conditional deletion of ATG5 in murine B cells results in reduced IgM and IgG responses in the setting
of both T-cell dependent and independent immunizations; further suggesting that autophagy is required
for B lymphocyte to plasma cell differentiation . Notably, ATG5 was also essential for the homing and/or
[52]
[52]
survival of long-lived plasma cells in the BM . Consistent with this, long-lived plasma cells were found to
[53]
highly express autophagic genes and display high basal levels of autophagy .
Autophagy as a mechanism of protein quality control
Plasma cells are professional antibody secreting cells (ASCs) uniquely optimized towards large-scale
immunoglobulin synthesis, folding, assembly, and secretion . Not unique to plasma cells, however, is the
[54]
fact that the protein synthesis process is intrinsically error prone. In fact, up to 30% of newly-synthesized
proteins are defective and need to be degraded [47,54] . Thus, an intricate balance between protein synthesis,
folding, and clearance must be maintained to prevent the accumulation of potentially toxic misfolded
proteins [47,54] . This is especially crucial for ASCs that cope with increased Ig synthesis by upregulating
[11]
folding capacity through the induction of unfolded protein response (UPR)-driven ER expansion .
However, when Ig synthesis exceeds folding capacity, the integrity of the proteome is preserved through
an interconnected network of protein quality control pathways which include the proteasome, autophagy,
aggresome, and UPR pathways . These pathways are so important to plasma cells that the amount of
[47]
newly-synthesized proteins degraded by the proteasome is 15-folds higher in plasma cells compared to
[55]
resting B-cells . Perhaps not surprisingly then, that MM, a cancer of plasma cells, exhibits the same
reliance on the protein quality control as evidenced by the clinical efficacy of proteasome inhibitors (PI).